Email updates

Keep up to date with the latest news and content from Stem Cell Research & Therapy and BioMed Central.

Highly Accessed Review

The less-often-traveled surface of stem cells: caveolin-1 and caveolae in stem cells, tissue repair and regeneration

Natasha Baker and Rocky S Tuan*

Author Affiliations

Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, 450 Technology Drive, Pittsburgh, PA, 15219-3143, USA

For all author emails, please log on.

Stem Cell Research & Therapy 2013, 4:90  doi:10.1186/scrt276

The electronic version of this article is the complete one and can be found online at: http://stemcellres.com/content/4/4/90


Published:30 July 2013

© 2013 BioMed Central Ltd.

Abstract

Stem cells are an important resource for tissue repair and regeneration. While a great deal of attention has focused on derivation and molecular regulation of stem cells, relatively little research has focused on how the subcellular structure and composition of the cell membrane influences stem cell activities such as proliferation, differentiation and homing. Caveolae are specialized membrane lipid rafts coated with caveolin scaffolding proteins, which can regulate cholesterol transport and the activity of cell signaling receptors and their downstream effectors. Caveolin-1 is involved in the regulation of many cellular processes, including growth, control of mitochondrial antioxidant levels, migration and senescence. These activities are of relevance to stem cell biology, and in this review evidence for caveolin-1 involvement in stem cell biology is summarized. Altered stem and progenitor cell populations in caveolin-1 null mice suggest that caveolin-1 can regulate stem cell proliferation, and in vitro studies with isolated stem cells suggest that caveolin-1 regulates stem cell differentiation. The available evidence leads us to hypothesize that caveolin-1 expression may stabilize the differentiated and undifferentiated stem cell phenotype, and transient downregulation of caveolin-1 expression may be required for transition between the two. Such regulation would probably be critical in regenerative applications of adult stem cells and during tissue regeneration. We also review here the temporal changes in caveolin-1 expression reported during tissue repair. Delayed muscle regeneration in transgenic mice overexpressing caveolin-1 as well as compromised cardiac, brain and liver tissue repair and delayed wound healing in caveolin-1 null mice suggest that caveolin-1 plays an important role in tissue repair, but that this role may be negative or positive depending on the tissue type and the nature of the repair process. Finally, we also discuss how caveolin-1 quiescence-inducing activities and effects on mitochondrial antioxidant levels may influence stem cell aging.

Keywords:
Caveolae; Caveolin-1; Stem cells; Signal transduction; Cholesterol; Tissue repair; Regenerative medicine

Introduction

Stem cells are an important resource for tissue regeneration. Much stem cell research has focused on stem cell sourcing and stem cell regulation by external stimuli (reviewed in [1]). However, relatively little is known about the composition of the stem cell membrane, the organization of which can affect cell responses to external stimuli. Specifically, membrane lipid rafts are recognized as important platforms regulating activity at the cell surface. These cholesterol-rich and sphingolipid-rich liquid-ordered phases in the cell membrane allow compartmentalization and clustering of signaling molecules [2,3]. Concentration of signaling molecules in membrane rafts may enable amplification, cross-talk, specificity or inhibitory regulation of cell signaling. One flask-shaped subtype of membrane raft, the caveola [4,5], is the regulation center for a plethora of cell signaling events owing to the activity of its distinguishing caveolin scaffolding proteins [6]. There are three caveolin proteins, which are essential for caveolae formation, cholesterol binding [7-10] and cholesterol trafficking [10-12]. As shown in Figure 1, the caveolin proteins form a hairpin loop in the cell membrane with their N-termini and C-termini remaining in the cell cytoplasm [13,14]. The cytoplasmic portion of the caveolin protein contains a caveolin scaffolding domain sequence that can bind to many different cell signaling molecules and effect cell signal transduction (reviewed in [6,15]).

thumbnailFigure 1. Structure and general activities of caveolae/caveolin-1. Structure (box): caveolae are flask-shaped invaginations in the cell membrane coated with multimers of caveolin scaffolding proteins. The N-termini and C-termini of caveolin proteins are in the cell cytoplasm, but a hairpin loop of the protein is inserted into the cell membrane. Caveolin-1 has a caveolin scaffolding domain (CSD) that can bind to and affect the activity of a variety of cell signaling molecules. Activities: various caveolae/caveolin-1 activities that have been reported in different cell types are depicted. Caveolin-1 binds to cholesterol and can regulate mitochondrial levels of cholesterol. Caveolae are rich cholesterol stores as well as membrane reservoirs that can stretch to buffer mechanical and osmotic stress at the cell surface. Caveolin-1 can regulate cellular levels of nitric oxide (NO) through regulation of NO synthase activity. Caveolin-1 can inhibit cell growth and activate cell senescence by inhibition of mitogen-activated protein (MAP) kinases and binding to the p53 inhibitor MdM2. Caveolin-1 can also regulate other growth and differentiation signaling pathways by caveolar endocytosis of cell surface receptors and sequestering secondary messengers such as β-catenin. Caveolin-1 also participates in focal adhesion signaling and internalization of integrins upon cell detachment. For references, see main text. BMP, bone morphogenetic protein; MLC, myosin light chain; PI-3-kinase, phosphatidylinositol 3-kinase; TGFβ, transforming growth factor beta.

Caveolae are particularly abundant in adipocytes, endothelial cells, pulmonary type I cells and muscle cells [10]. Assays of various mouse and rat tissues have determined that caveolin-1 is most highly expressed in fat and lung tissue [16-20], but it is also expressed in many other tissues and differentiated cell types [18,19,21-28]. Caveolin-2 is usually co-expressed with caveolin-1 and appears unable to form caveolae in the absence of caveolin-1 [17,18,29]. Caveolin-3, meanwhile, is highly expressed in muscle cells [19,22,30].

Given its expression in many cell types, the role of caveolin-1 in cell activities has been well researched. The growth factor receptors and signaling molecules that localize to caveolae and/or interact with caveolin-1 include the platelet-derived growth factor receptor and the epidermal growth factor (EGF) receptor, G-protein coupled receptors, G-protein alpha and beta subunits, Src, endothelial nitric oxide synthase, and proteins in the Ras-p42/44 mitogen-activated protein kinase and phosphatidylinositol 3-kinase–Akt pathways [6,15]. While association of signaling molecules with caveolin-1 is usually inhibitory [6,15], signaling can be enhanced, probably by bringing molecules in close proximity to one another [31]. Furthermore, binding to the caveolin-1 scaffolding domain may enhance the activity of some enzymes. This has been demonstrated in vitro with the insulin receptor kinase [32]. Figure 1 summarizes functions attributed to caveolae and caveolin-1 in various cell types. If present in stem cells, many of these activities could impact stem cell behavior. This review discusses current research findings that implicate caveolin-1 in the regulation of stem and progenitor cell activity, tissue repair and aging.

Caveolin-1 regulation of cell proliferation

Inhibitory association of signaling molecules with caveolin-1, as well as caveolin-1 regulation of intracellular cholesterol levels [33], may be responsible for the mostly inhibitory effects of caveolin-1 on differentiated cell proliferation [29,34-38]. In the caveolin-1 null mouse, enlarged populations of cells expressing stem cell markers in the gut, mammary gland and brain have been observed [39-41], suggesting that caveolin-1 may also negatively regulate stem cell proliferation. Furthermore, others have noted that the bone marrow-derived mesenchymal stem cells (MSCs) from the caveolin-1 null mouse have a higher proliferative rate in culture [42], and in mouse neural progenitor cells caveolin-1 facilitates glucocorticoid receptor signaling that leads to inhibition of proliferation [43]. Meanwhile, in human MSCs, Park and colleagues showed that caveolin-1 expression increases when cells are cultured to senescence [44], suggesting that caveolin-1 expression is inversely associated with the proliferative rate of human MSCs. In agreement, we have shown that siRNA-mediated knockdown of caveolin-1 expression in human MSCs increases their proliferation [45].

Conversely, in mouse embryonic stem cells (ESCs), caveolin-1 and caveolae structure appear to be required for cell renewal. Treatment of ESCs with caveolin-1 siRNA or with methyl-β-cyclodextrin, which depletes membrane cholesterol thus disrupting the caveolae structure, reduces the cell proliferation index [46]. Furthermore, when mouse ESCs are seeded on fibronectin, caveolin-1 phosphorylation and caveolae integrity are required in downstream events that activate DNA synthesis [47]. Caveolin-1 also mediates estradiol-17β-induced cell proliferation [48] and its expression is required for EGF-induced cell proliferation and glucose induction of DNA synthesis in ESCs [49]. Caveolin-1 may therefore negatively regulate the proliferation of adult murine and human progenitor cells, but in murine ESCs caveolin-1 may be positively involved in proliferative signaling.

Caveolin-1 effects on cell differentiation

Caveolin-1 is known to regulate Wnt/β-catenin signaling [50-54], transforming growth factor beta signaling [55-62] and bone morphogenetic protein (BMP) signaling [63-67], all pathways that can guide stem cell fate. Meanwhile, caveolin expression typically increases upon cell differentiation in vitro[16-20,23,30,68-72], including upon osteogenic differentiation of human MSCs [45] and neurogenesis of rat MSCs [73]. This may reflect negative feedback, where caveolin-1 expression increases as cells differentiate to stabilize the phenotype and prevent continued growth and differentiation. For example, bone marrow MSCs from the caveolin-1 null mouse have greater osteogenic potential [74], suggesting that caveolin-1 inhibits osteogenesis. This may explain the increased postnatal bone formation rate in these animals [74]. We have also shown that caveolin-1 knockdown enhances human MSC osteogenesis [45]. Caveolin-1 also inhibits murine and rat neuronal and oligodendral differentiation [73,75,76] and human MSC adipogenesis [44].

Caveolin-1 regulation of differentiation probably occurs within caveolae through interactions with receptors and downstream signaling molecules for differentiation stimuli. In accordance with this idea, MSC osteogenic differentiation can be promoted by the cholesterol biosynthesis inhibitor simvastatin [77-79], and by oxysterols, which suppress caveolin-1 expression and cause caveolin-1 translocation out of caveolae [80,81]. Also, bone marrow MSCs isolated from mouse models of osteoporosis or high bone mineral density have decreased and increased responsiveness to BMP2, respectively, due to dysregulated localization of the BMP receptor 1a with caveolin-1 isoforms, and dysregulated caveolae trafficking in response to BMP2 [82,83]. Caveolae endocytosis of BMP receptors can also affect rat MSC differentiation [84] (as described further below) and active β-catenin levels are elevated in cells expressing stem cell markers in the intestinal crypts and mammary gland of the caveolin-1 null mouse [39,40], while caveolin-1 regulation of neurogenesis may occur via effects on Notch signaling [73].

Caveolin-1/caveolae regulation of matrix-directed stem cell differentiation

Engler and colleagues showed that MSCs can differentiate according to their substratum elasticity [85]. MSCs seeded on a soft substrate with an elastic modulus similar to brain tissue differentiate into nerve cells, while MSCs seeded on a substrate with an elastic modulus similar to bone differentiate into osteoblasts, and those seeded on a substrate with an elastic modulus similar to muscle differentiate into myoblasts [85]. This phenomenon depends on nonmuscle myosin II activity [85]. As summarized in Figure 2, Du and colleagues have shown that, at least on soft substrates, the mechanism involves caveolin-1 and caveolar endocytosis [84]. In MSCs seeded on a soft substrate, there is increased activation and internalization of β1-integrin via caveolae endocytosis. BMP receptor 1a co-localized with β1-integrin is consequently also internalized, thus inhibiting pro-osteogenic BMP signaling [84]. Du and colleagues calculated that integrin adhesions to the substratum should be more easily ruptured on soft than on stiff substrates [84]. Therefore, when an adherent cell pulls on (or deforms) its matrix, more integrin contacts should be ruptured if that matrix is soft. Ruptured integrin contacts may then be endocytosed in caveolae [84]. In sum, this means tensile forces generated by nonmuscle myosin II when a cell deforms its matrix could be coupled to caveolar endocytosis to modulate availability of cell signaling platforms necessary for directing cell differentiation.

thumbnailFigure 2. Caveolae endocytosis helps couple regulation of differentiation signals to culture substrate elasticity. When mesenchymal stem cells are seeded on a stiff substrate with an elastic modulus similar to bone, focal adhesions and stress fibers form and nonmuscle myosin II expression increases. Cells osteogenically differentiate on the stiff substrate. The activity of nonmuscle myosin II, which promotes the assembly of focal adhesions, is required for substrate-driven differentiation. As nonmuscle myosin II expression increases in cells seeded on a stiff substrate, it may allow cells to form more focal adhesions and generate the greater force needed to deform a stiff matrix. When cells are seeded on a soft substrate, the integrin contacts with the substrate may be easily ruptured by nonmuscle myosin II-generated forces on the cell cytoskeleton. Expression of nonmyosin II remains lower and less focal adhesions and stress fibers form than in cells seeded on a stiff substrate. Activated integrins from ruptured contacts with the substrate are internalized by caveolar endocytosis. The bone morphogenetic protein receptor 1a (BMPR1a) is co-internalized and the potential for pro-osteogenic bone morphogenetic protein (BMP)-induced Smad signaling is reduced as a result. Cells neurogenically differentiate on the soft substrate. For more information, refer to [84,85].

Intriguingly, culture of muscle stem cells on substrates with a similar rigidity to muscle improves their viability and proliferation in culture and maintains their stemness and regenerative potential [86]. Thus, stem cells possibly respond to changes in matrix elasticity only when it is different to their tissue of origin [85]. The mechanism behind this and the potentially important role of caveolae is a very interesting topic that deserves further exploration.

Meanwhile, it is interesting to note that caveolin-1 may promote astroglial differentiation [87] and is required for human microvascular endothelial cell tubule formation in a Matrigel differentiation assay [70]. Perhaps this observation indicates that caveolin-1 inhibition of some signaling pathways protects or promotes activation of other pathways. We have found that knockdown of caveolin-1 expression in MSCs decreases mRNA expression of the pluripotency marker POU5F1/Oct4 (unpublished observations), and others have found that caveolin-1 expression and caveolae structure are important for maintaining mouse ESC expression of pluripotency markers (Oct4, Sox2, FoxD3, Rex1) [46]. One could hypothesize that caveolin-1 may act to maintain the stemness of MSCs by holding growth factor receptors and signaling molecules in an inhibited state in caveolae, and/or committing them to caveolar endocytosis. Meanwhile, alterations to caveolin-1 expression or activity may release inhibition of signaling molecules to allow MSCs to be more responsive to other growth and differentiation stimuli. Then, as MSCs differentiate, caveolin-1 expression may increase dramatically to stabilize the new phenotype and prevent continued differentiation. This idea is schematically summarized in Figure 3A. Coupling the activity of caveolin-1 and caveolae to cell–matrix interactions would be one way to couple caveolin-1/caveolae regulatory activity on differentiation signals to a cell’s environment. Another way caveolin-1/caveolae activity may be controlled is via cholesterol, which is discussed later.

thumbnailFigure 3. Caveolin-1 stabilization of cell phenotype. (A) Hypothesized role for caveolin-1 and caveolae in contributing to the control of cell growth and differentiation. In undifferentiated quiescent stem cells, low levels of caveolin-1 are expressed. Caveolin-1 binding to growth and differentiation receptors and their secondary messengers within caveolae may suppress signaling. A decrease in caveolin-1 expression at the cell surface (perhaps triggered by chemical signals and/or nonmuscle myosin II activity) leads to receptor and signaling protein redistribution. Consequently, stem cells enter a pre-differentiation state more able to respond to growth and differentiation cues. Upon cell differentiation, caveolin-1 expression increases dramatically. Receptors and their secondary messengers are re-captured by caveolae to confine or internalize them and prevent continued growth. MSC, mesenchymal stem cell. (B) Proposed role for caveolin-1 in the control of mammary gland development based on in vitro and in vivo observations [88,89]. Prolactin, estrogen and progesterone compete to control caveolin-1 expression. Caveolin-1 inhibits prolactin signaling by binding to the prolactin receptor-associated kinase Jak2. At birth, levels of prolactin are high and levels of estrogen and progesterone drop. Prolactin is thus able to suppress caveolin-1 expression, positively feeding back on its own signaling pathway by releasing Jak2 from caveolin-1 inhibition. The elevation in prolactin signaling triggers mammary gland development.

In cells where caveolin-1 activity inhibits growth and differentiation, a transient decrease in caveolin-1 expression or low caveolin-1 activity should be required for cell proliferation and differentiation to be activated. Studies investigating mammary gland development support this idea (Figure 3B). The hormone prolactin, which activates the growth and differentiation of the mammary epithelium during pregnancy and lactation, suppresses caveolin-1 expression during lactation in mice [88]. In HC11 cells (used as a model of mammary epithelial cell differentiation), caveolin-1 inhibits prolactin signaling by binding and retaining the prolactin receptor-associated kinase Jak2 in caveolae [89]. Caveolin-1 inhibition of prolactin signaling may also occur in vivo, as during pregnancy the caveolin-1 null mouse mammary gland shows dramatically accelerated lobuloalveolar development, early milk production and a premature lactation phenotype [89]. Furthermore, in immortalized primary human mammary epithelial cells, estrogen and progesterone together upregulate caveolin-1 expression, and the authors of these findings have proposed that in vivo the drop in these hormones upon birth (when prolactin levels are high) is responsible for de-repression of prolactin signaling and decreased caveolin-1 expression during lactation [89]. In summary, this hypothesis is an example where transient, carefully timed regulation of caveolin-1 expression is important for cell differentiation (summarized in Figure 3B).

Caveolin-1 effects on tissue repair

If transient downregulation of caveolin-1 expression/activity is required for cell proliferation and differentiation, it may also be required for tissue repair. Volonte and colleagues have shown that such temporal changes in caveolin expression occur during tissue regeneration in skeletal muscle [90]. Caveolin-1 is expressed in muscle satellite cells in mice and in myogenic precursor cells in vitro[90]. Downregulation of caveolin-1 expression in these cells was shown to be a pre-requisite for their proliferation, migration and differentiation to repair muscle wounds in vivo and in vitro[90]. Following myogenic differentiation, caveolin-3 is expressed in mature multinucleated myotubes, and caveolin-1 is re-expressed in undifferentiated myogenic precursor cells that surround myotubes after wound healing is complete [90] (summarized in Figure 4A). This event agrees with a requirement for transient downregulation in caveolin expression for progenitor cell proliferation and differentiation to mediate tissue repair. Further supporting this idea, muscle regeneration is delayed in caveolin-1 overexpressing mice [90] and caveolin-1-overexpressing myogenic precursor cells fail to differentiate, to migrate and to proliferate to repair wounds in vitro[90].

thumbnailFigure 4. Temporal regulation of caveolin-1 during repair processes. (A) Muscle satellite cells. Studies by Volonte and colleagues suggest a decrease in caveolin-1 expression is required for satellite cells to proliferate and migrate to damaged muscle fibers and initiate repair [90]. Once migrated, satellite cells form myotubes and muscle-specific caveolin-3 is expressed. (B) Schwann cells. When Schwann cells de-differentiate in response to injury, caveolin-1 expression decreases [92], possibly allowing cell proliferation to repair injury to the myelin sheath.

There are other examples of drops in caveolin expression during reparative processes. For example, in the corneal epithelium, levels of caveolin-1 expression are inversely related to wound healing capacity [91]. In the rat sciatic nerve, caveolin-1 expression also increases as Schwann cells differentiate into a myelinating phenotype, but decreases upon their de-differentiation in response to injury [92]. This may occur because caveolin-1 is only present in the differentiated Schwann cell, with a functional role in cholesterol transport, and/or occur because the drop in caveolin-1 expression allows cells to proliferate in response to injury [92] (Figure 4B). Meanwhile, caveolin-1 appears to inhibit rat fetal neural progenitor cell neuronal differentiation, and downregulation in caveolin-1 occurs in these cells upon hypoxia-induced neuronal differentiation [76].

Caveolin-1 expression is also reduced in mouse hearts 3 days following cryoinjury [93]. The return of caveolin-1 expression to normal levels is important for later stages of cardiac repair, however, suggestive of a positive role for caveolin-1 in part of the process [93]. Also, in rat heart tissue, translocation of caveolin-3 and the caveolin-1α isoform out of caveolae upon aging or infarction may contribute to tissue degeneration/disease pathology [94], while the caveolin-1 scaffolding domain can protect against polymorphonuclear neutrophil reperfusion injury [95]. Caveolin proteins may thus be positively involved in the maintenance of healthy heart tissue. Caveolin-1 may be particularly important for repair in the cardiovascular system, because it is required for the formation of new blood vessels [21,96]. In contrast to its anti-proliferative role in most other cell types, caveolin-1 is needed for the induction of mouse pulmonary microvascular endothelial cell proliferation in response to a disruption in laminar flow [97]. The requirement for caveolin-1 in new blood vessel formation may be a reason why caveolin-1 is vital for collateralization following ischemia in tissues such as the hindlimb [98] and why caveolin-1 deficiency can lead to an increased infarction volume upon cerebral ischemia [99].

Liver regeneration is another example where caveolin-1 may actually be required for cell proliferation and tissue repair. Caveolin-1 null mice have reduced survival after partial hepatectomy [100], and those that survive have a greatly reduced liver regeneration index compared with controls [100]. Caveolin-1 appears to be required for lipid droplet formation, a crucial step in the proliferative response of hepatocytes during liver regeneration [100]. A lack of caveolin-1 regulation of mitochondrial cholesterol levels in these mice has also been suggested to impair metabolism (and thus affect proliferation) to contribute to the phenotype [12]. However, others have found that caveolin-1 is dispensable for liver regeneration in mice [101] and that caveolin-1 deficiency even accelerates liver regeneration [102]. This discrepancy in results could be due to the use of two different knockout animals [100,101]. Meanwhile, caveolin-1 may also have a positive role in regeneration in the kidney; it is expressed in regenerating proximal tubules after gentamicin-induced acute renal failure in rats and may have a role in the regenerative process by modulating EGF and platelet-derived growth factor signaling [103]. Indeed, perhaps in cases where caveolin-1 is required for repair and regeneration, caveolin-1 inhibition of other pathways is beneficial for signal pathways that activate repair.

Caveolin-1 may also have a positive role in cutaneous wound healing. Endocytosis of β1-integrins in fibroblasts occurs via a pathway involving syndecan-4, protein kinase C alpha, RhoG and caveolin-1, and this process is crucial for fibroblast recruitment and migration during wound healing [104]. Indeed, caveolin-1 null mice have significantly slower skin wound healing than wild-type mice [105]. Caveolin-1 may also have a positive role in regulating the formation of the lipid-rich outermost layer of the epidermis following injury by promoting keratinocyte terminal differentiation (programmed cell death) into corneocytes [106].

In summary, caveolin-1 may positively or negatively contribute to tissue repair depending on the tissue. This context dependence is possibly due to caveolin-1-negative and caveolin-1-positive regulation of different cell signaling pathways, but much further research is required to understand the role of caveolin-1 in tissue repair.

Caveolin-1 regulation of stem cell homing and mobilization

Migration is an important aspect of stem cell function. Caveolin-1 has an important role in promoting directional cell migration in other cell types (reviewed in [107]), and may also be involved in stem cell migration. Caveolin-1 expression is required for EGF and fibronectin-induced migration of ESCs [49,108] and may also affect stem cell mobilization and homing. Caveolin-1 expression appears to enhance murine renal MSC adhesion to post-ischemic renal tissue [109]. This adhesion occurs via interaction of stem cell CXCR4 receptors with stromal cell-derived factor-1 on the target cell, and α4β1(VLA4)–vascular cell adhesion molecule-1 interactions [109]. Caveolin-1 may be required for CXCR4 interactions (Figure 5A), because membrane rafts are important for CXCR4–stromal cell-derived factor-1 interactions in human CD34+ hematopoietic stem/progenitor cells [110]. Meanwhile, as summarized in Figure 5B, studies by Sbaa and colleagues suggest caveolin-1 expression is required for mobilization of progenitor cells from bone marrow reserves in mice [111]. In vitro experiments suggest this may be because caveolar internalization of CXCR4 receptors in response to soluble stromal cell-derived factor-1 may be important for progenitor cell mobilization [111].

thumbnailFigure 5. Caveolin-1 regulation of progenitor cell homing and mobilization. (A) Renal stem cell homing. Caveolin-1 may positively contribute to renal stem cell adhesion to ischemic tissue [109], possibly by promoting CXCR4 clustering in caveolae and allowing its interaction with stromal cell-derived factor-1 (SDF-1) in the ischemic tissue. (B) Bone marrow stem cell mobilization. In the bone marrow, caveolar internalization of CXCR4 may be important for progenitor cell de-adhesion to marrow stromal cells. Upon tissue ischemia, endothelial progenitor cells from the bone marrow may be recruited to the ischemic site to form new vasculature to restore blood flow. Caveolin-1 null mice (Cav−/−), unlike wild-type (WT) mice, fail to restore perfusion when ischemia is induced in their hind limbs. However, this phenotype can be rescued by direct intravenous infusion of Cav−/− or WT progenitor cells in the affected area, or by transplanting WT bone marrow into irradiated Cav−/− mice [111]. These results suggest that caveolin-1 is involved in the process of progenitor cell mobilization from the bone marrow in response to soluble SDF-1, which normally triggers progenitor cell mobilization. HSPC, hematopoietic stem/progenitor cell; MSC, mesenchymal stem cell.

Aging

Traditionally, reactive oxygen species-mediated damage to cellular components has been thought to cause aging [112]. Caveolin-1 can protect against oxidative stress by regulating mitochondrial cholesterol levels, which affect the levels of the antioxidant glutathione in mitochondria [113] (Figure 1). Accordingly, the accumulation of mitochondrial cholesterol and reactive oxygen species in the liver and brain of caveolin-1 null mice contributes to disease progression in degenerative disease models (steatohepatitis, Huntington’s disease, Alzheimer’s disease) [113], and these animals demonstrate some signs of accelerated aging, particularly in the brain [114,115]. This aging may be due to decreased brain mitochondrial glutathione levels [113]. However, the aging may also or solely be due to increased production of amyloid-β protein from amyloid precursor protein, the processing of which is normally regulated in membrane rafts [114]. Meanwhile, it is now clear that reactive oxygen species do not initiate aging and that, although they may have damaging effects on macromolecules, they may have beneficial effects on age-related cell signaling [116].

A positive role for caveolin-1 in aging agrees more with the mostly quiescent effects of caveolin-1 on cell biology discussed above. Also, caveolin-1 promotes insulin signaling and adipocyte lipid droplet storage [117-119]. Caveolin-1 could therefore have a general role in inhibiting continued growth and differentiation and slowing metabolism, perhaps as a response to completion of tissue formation and aging. In turn, this may mean that reducing caveolin-1 expression/activity could reverse aging effects in certain cells/tissues. Indeed, caveolin-1 expression increases with age in a number of rat tissues and in human diploid fibroblasts [120], and reducing caveolin-1 expression in the latter restores responsiveness to EGF [121]. Moreover, caveolin-1 null mice are lean, resistant to diet-induced obesity [119], insulin resistant [118] and have decreased levels of the adipokine leptin [119]. Conversely, plasma levels of leptin are increased in aged mice [122] and reducing the activity of nutrient sensing pathways (for example, insulin signaling) is known to increase longevity in several species [123]. In humans, insulin resistance is a side effect of treatment with rapamycin, the inhibitor of mammalian target of rapamycin [124], which is known to slow aging in mice [125,126]. Whether rapamycin’s anti-aging effects could be partly attributed to inhibition of caveolin-1/caveolae activity remains to be elucidated and warrants further investigation; one would not be surprised if caveolin-1 could affect stem cell aging, which rapamycin has been shown to do [126].

The activation of stem cells is dysregulated with age in mouse muscle [127-129] and, as Volonte and colleagues have shown that caveolin-1 expression delays murine skeletal muscle regeneration [90], one could hypothesize that an age-related increase in caveolin-1 expression may be responsible for an age-related decline in mouse muscle regenerative potential. Interestingly, aged satellite cells have impaired activation of Notch-Delta signaling [128], and premature activation of Wnt signaling in these cells causes fibrosis [129]. Caveolin-1 can affect the propagation of both Wnt and Notch signaling pathways in other progenitor cells [39,40,73,87]. Furthermore, parabiotic pairings of old rats with young rats increases aortal and muscle cholesterol uptake in the older animals [130]. An increase in intracellular cholesterol levels promotes caveolin-1-directed cholesterol efflux and caveolae formation, and free cholesterol promotes caveolin-1 expression [33,80]. Perhaps older tissues thus have a greater tendency to absorb cholesterol, which in turn increases caveolin-1 activity and caveolae formation. Meanwhile, systemic factors released by young mice can reactivate resident stem cells in aged mice and replenish their reparative capacity [128]. One would therefore be interested to determine whether factors in young plasma affect cholesterol metabolism and caveolae activity in old cells.

Mechanosensing

Mechanical stimulation and focal adhesion signaling can regulate stem cell differentiation [131], including fluid shear forces at the surface of the cell [132]. Caveolae and caveolin-1 are important for mechanosensing and the propagation of mechanotransduction pathways in many cell types, particularly cells exposed to shear forces [133-144]. The actual structure of caveolae even provides a membrane reserve that can buffer stresses on the cell membrane caused by mechanical stretch and osmotic swelling [145-147] (as shown in Figure 1). The role of caveolae and caveolin-1 in stem cell mechano-responses may therefore also be worth investigation. Perhaps it is possible that mechanical perturbations to caveolae can activate differentiation and proliferation and repair pathways in quiescent stem cells.

Conclusions

In summary, caveolin-1 affects several aspects of stem cell biology, including proliferation, differentiation, substrate-driven differentiation, homing and mobilization. We predict that alteration to caveolin-1/caveolar activity is a prerequisite for stem cell activation and differentiation, and that increased caveolin-1 expression with age may implicate the protein in age-related declines in tissue regenerative potential. However, because of the multiple (and probably context-dependent) effects of caveolin-1, this will not apply to all cells and tissues. Promotion of caveolin-1 activity may be desirable for some areas of regenerative medicine (for example, mobilization of bone marrow stores of progenitor cells), while inhibition may be desirable in others (for example, to reverse muscle aging, increase bone density, or improve in vitro expansion of adult stem cell harvests). Manipulation of caveolin-1 expression/activity may be possible in specific tissues in vivo; for example, via siRNA approaches or modulation of cholesterol biosynthesis. However, much research is required to define caveolin-1 function in different stem cells and to determine whether manipulation of membrane signaling platforms such as caveolae could be beneficial in stem cell therapies and regenerative medicine.

Abbreviations

BMP: Bone morphogenetic protein; EGF: Epidermal growth factor; ESC: Embryonic stem cell; MSC: Mesenchymal stem cell; siRNA: Small interfering RNA.

Competing interests

The authors declare that they have no competing interests.

Acknowledgements

Supported in part by a grant from the Commonwealth of Pennsylvania Department of Health (SAP 4100050913).

References

  1. Discher DE, Mooney DJ, Zandstra PW: Growth factors, matrices, and forces combine and control stem cells.

    Science 2009, 324:1673-1677. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  2. Simons K, Toomre D: Lipid rafts and signal transduction.

    Nat Rev Mol Cell Biol 2000, 1:31-39. PubMed Abstract | Publisher Full Text OpenURL

  3. Simons K, Ikonen E: Functional rafts in cell membranes.

    Nature 1997, 387:569-572. PubMed Abstract | Publisher Full Text OpenURL

  4. Yamada E: The fine structure of the gall bladder epithelium of the mouse.

    J Biophys Biochem Cytol 1955, 1:445-458. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  5. Palade GE: Fine structure of blood capillaries.

    J Appl Phys 1953, 24:1424-1424. OpenURL

  6. Patel HH, Murray F, Insel PA: Caveolae as organizers of pharmacologically relevant signal transduction molecules.

    Annu Rev Pharmacol Toxicol 2008, 48:359-391. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  7. Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG: Caveolin, a protein component of caveolae membrane coats.

    Cell 1992, 68:673-682. PubMed Abstract | Publisher Full Text OpenURL

  8. Fra AM, Williamson E, Simons K, Parton RG: De novo formation of caveolae in lymphocytes by expression of VIP21-caveolin.

    Proc Natl Acad Sci USA 1995, 92:8655-8659. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  9. Murata M, Peranen J, Schreiner R, Wieland F, Kurzchalia TV, Simons K: VIP21/caveolin is a cholesterol-binding protein.

    Proc Natl Acad Sci USA 1995, 92:10339-10343. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  10. Fielding CJ, Fielding PE: Cholesterol and caveolae: structural and functional relationships.

    Biochim Biophys Acta 2000, 1529:210-222. PubMed Abstract | Publisher Full Text OpenURL

  11. Ikonen E, Parton RG: Caveolins and cellular cholesterol balance.

    Traffic 2000, 1:212-217. PubMed Abstract | Publisher Full Text OpenURL

  12. Bosch M, Mari M, Gross SP, Fernandez-Checa JC, Pol A: Mitochondrial cholesterol: a connection between caveolin, metabolism, and disease.

    Traffic 2011, 12:1483-1489. PubMed Abstract | Publisher Full Text OpenURL

  13. Dupree P, Parton RG, Raposo G, Kurzchalia TV, Simons K: Caveolae and sorting in the trans-Golgi network of epithelial cells.

    EMBO J 1993, 12:1597-1605. PubMed Abstract | PubMed Central Full Text OpenURL

  14. Monier S, Parton RG, Vogel F, Behlke J, Henske A, Kurzchalia TV: VIP21-caveolin, a membrane protein constituent of the caveolar coat, oligomerizes in vivo and in vitro.

    Mol Biol Cell 1995, 6:911-927. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  15. Krajewska WM, Maslowska I: Caveolins: structure and function in signal transduction.

    Cell Mol Biol Lett 2004, 9:195-220. PubMed Abstract | Publisher Full Text OpenURL

  16. Scherer PE, Lisanti MP, Baldini G, Sargiacomo M, Mastick CC, Lodish HF: Induction of caveolin during adipogenesis and association of GLUT4 with caveolin-rich vesicles.

    J Cell Biol 1994, 127:1233-1243. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  17. Scherer PE, Okamoto T, Chun M, Nishimoto I, Lodish HF, Lisanti MP: Identification, sequence, and expression of caveolin-2 defines a caveolin gene family.

    Proc Natl Acad Sci USA 1996, 93:131-135. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  18. Scherer PE, Lewis RY, Volonte D, Engelman JA, Galbiati F, Couet J, Kohtz DS, van Donselaar E, Peters P, Lisanti MP: Cell-type and tissue-specific expression of caveolin-2. Caveolins 1 and 2 co-localize and form a stable hetero-oligomeric complex in vivo.

    J Biol Chem 1997, 272:29337-29346. PubMed Abstract | Publisher Full Text OpenURL

  19. Song KS, Scherer PE, Tang Z, Okamoto T, Li S, Chafel M, Chu C, Kohtz DS, Lisanti MP: Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins.

    J Biol Chem 1996, 271:15160-15165. PubMed Abstract | Publisher Full Text OpenURL

  20. Kandror KV, Stephens JM, Pilch PF: Expression and compartmentalization of caveolin in adipose cells: coordinate regulation with and structural segregation from GLUT4.

    J Cell Biol 1995, 129:999-1006. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  21. Griffoni C, Spisni E, Santi S, Riccio M, Guarnieri T, Tomasi V: Knockdown of caveolin-1 by antisense oligonucleotides impairs angiogenesis in vitro and in vivo.

    Biochem Biophys Res Commun 2000, 276:756-761. PubMed Abstract | Publisher Full Text OpenURL

  22. Hagiwara Y, Nishina Y, Yorifuji H, Kikuchi T: Immunolocalization of caveolin-1 and caveolin-3 in monkey skeletal, cardiac and uterine smooth muscles.

    Cell Struct Funct 2002, 27:375-382. PubMed Abstract | Publisher Full Text OpenURL

  23. Galbiati F, Volonte D, Gil O, Zanazzi G, Salzer JL, Sargiacomo M, Scherer PE, Engelman JA, Schlegel A, Parenti M, Okamoto T, Lisanti MP: Expression of caveolin-1 and −2 in differentiating PC12 cells and dorsal root ganglion neurons: caveolin-2 is up-regulated in response to cell injury.

    Proc Natl Acad Sci USA 1998, 95:10257-10262. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  24. Cameron PL, Ruffin JW, Bollag R, Rasmussen H, Cameron RS: Identification of caveolin and caveolin-related proteins in the brain.

    J Neurosci 1997, 17:9520-9535. PubMed Abstract | Publisher Full Text OpenURL

  25. Lofthouse RA, Davis JR, Frondoza CG, Jinnah RH, Hungerford DS, Hare JM: Identification of caveolae and detection of caveolin in normal human osteoblasts.

    J Bone Joint Surg Br 2001, 83:124-129. PubMed Abstract | Publisher Full Text OpenURL

  26. Solomon KR, Adolphson LD, Wank DA, McHugh KP, Hauschka PV: Caveolae in human and murine osteoblasts.

    J Bone Miner Res 2000, 15:2391-2401. PubMed Abstract | Publisher Full Text OpenURL

  27. Schwab W, Galbiati F, Volonte D, Hempel U, Wenzel KW, Funk RH, Lisanti MP, Kasper M: Characterisation of caveolins from cartilage: expression of caveolin-1, -2 and −3 in chondrocytes and in alginate cell culture of the rat tibia.

    Histochem Cell Biol 1999, 112:41-49. PubMed Abstract | Publisher Full Text OpenURL

  28. Schwab W, Kasper M, Gavlik JM, Schulze E, Funk RH, Shakibaei M: Characterization of caveolins from human knee joint cartilage: expression of caveolin-1, -2, and −3 in chondrocytes and association with integrin beta1.

    Histochem Cell Biol 2000, 113:221-225. PubMed Abstract | Publisher Full Text OpenURL

  29. Razani B, Engelman JA, Wang XB, Schubert W, Zhang XL, Marks CB, Macaluso F, Russell RG, Li M, Pestell RG, Di Vizio D, Hou H Jr, Kneitz B, Lagaud G, Christ GJ, Edelmann W, Lisanti MP: Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities.

    J Biol Chem 2001, 276:38121-38138. PubMed Abstract | Publisher Full Text OpenURL

  30. Tang Z, Scherer PE, Okamoto T, Song K, Chu C, Kohtz DS, Nishimoto I, Lodish HF, Lisanti MP: Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle.

    J Biol Chem 1996, 271:2255-2261. PubMed Abstract | Publisher Full Text OpenURL

  31. Lisanti MP, Scherer PE, Tang Z, Sargiacomo M: Caveolae, caveolin and caveolin-rich membrane domains: a signalling hypothesis.

    Trends Cell Biol 1994, 4:231-235. PubMed Abstract | Publisher Full Text OpenURL

  32. Yamamoto M, Toya Y, Schwencke C, Lisanti MP, Myers MG Jr, Ishikawa Y: Caveolin is an activator of insulin receptor signaling.

    J Biol Chem 1998, 273:26962-26968. PubMed Abstract | Publisher Full Text OpenURL

  33. Fielding CJ, Bist A, Fielding PE: Intracellular cholesterol transport in synchronized human skin fibroblasts.

    Biochemistry 1999, 38:2506-2513. PubMed Abstract | Publisher Full Text OpenURL

  34. Fujita Y, Maruyama S, Kogo H, Matsuo S, Fujimoto T: Caveolin-1 in mesangial cells suppresses MAP kinase activation and cell proliferation induced by bFGF and PDGF.

    Kidney Int 2004, 66:1794-1804. PubMed Abstract | Publisher Full Text OpenURL

  35. Koleske AJ, Baltimore D, Lisanti MP: Reduction of caveolin and caveolae in oncogenically transformed cells.

    Proc Natl Acad Sci USA 1995, 92:1381-1385. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  36. Engelman JA, Wykoff CC, Yasuhara S, Song KS, Okamoto T, Lisanti MP: Recombinant expression of caveolin-1 in oncogenically transformed cells abrogates anchorage-independent growth.

    J Biol Chem 1997, 272:16374-16381. PubMed Abstract | Publisher Full Text OpenURL

  37. Galbiati F, Volonte D, Engelman JA, Watanabe G, Burk R, Pestell RG, Lisanti MP: Targeted downregulation of caveolin-1 is sufficient to drive cell transformation and hyperactivate the p42/44 MAP kinase cascade.

    EMBO J 1998, 17:6633-6648. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  38. Galbiati F, Volonte D, Liu J, Capozza F, Frank PG, Zhu L, Pestell RG, Lisanti MP: Caveolin-1 expression negatively regulates cell cycle progression by inducing G(0)/G(1) arrest via a p53/p21(WAF1/Cip1)-dependent mechanism.

    Mol Biol Cell 2001, 12:2229-2244. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  39. Li J, Hassan GS, Williams TM, Minetti C, Pestell RG, Tanowitz HB, Frank PG, Sotgia F, Lisanti MP: Loss of caveolin-1 causes the hyper-proliferation of intestinal crypt stem cells, with increased sensitivity to whole body gamma-radiation.

    Cell Cycle 2005, 4:1817-1825. PubMed Abstract | Publisher Full Text OpenURL

  40. Sotgia F, Williams TM, Cohen AW, Minetti C, Pestell RG, Lisanti MP: Caveolin-1-deficient mice have an increased mammary stem cell population with upregulation of Wnt/beta-catenin signaling.

    Cell Cycle 2005, 4:1808-1816. PubMed Abstract | Publisher Full Text OpenURL

  41. Jasmin JF, Yang M, Iacovitti L, Lisanti MP: Genetic ablation of caveolin-1 increases neural stem cell proliferation in the subventricular zone (SVZ) of the adult mouse brain.

    Cell Cycle 2009, 8:3978-3983. PubMed Abstract | Publisher Full Text OpenURL

  42. Case N, Xie Z, Sen B, Styner M, Zou M, O'Conor C, Horowitz M, Rubin J: Mechanical activation of beta-catenin regulates phenotype in adult murine marrow-derived mesenchymal stem cells.

    J Orthop Res 2010, 28:1531-1538. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  43. Samarasinghe RA, Di Maio R, Volonte D, Galbiati F, Lewis M, Romero G, DeFranco DB: Nongenomic glucocorticoid receptor action regulates gap junction intercellular communication and neural progenitor cell proliferation.

    Proc Natl Acad Sci USA 2011, 108:16657-16662. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  44. Park JS, Kim HY, Kim HW, Chae GN, Oh HT, Park JY, Shim H, Seo M, Shin EY, Kim EG, Park SC, Kwak SJ: Increased caveolin-1, a cause for the declined adipogenic potential of senescent human mesenchymal stem cells.

    Mech Ageing Dev 2005, 126:551-559. PubMed Abstract | Publisher Full Text OpenURL

  45. Baker N, Zhang G, You Y, Tuan RS: Caveolin-1 regulates proliferation and osteogenic differentiation of human mesenchymal stem cells.

    J Cell Biochem 2012, 113:3773-3787. PubMed Abstract | Publisher Full Text OpenURL

  46. Lee MY, Ryu JM, Lee SH, Park JH, Han HJ: Lipid rafts play an important role for maintenance of embryonic stem cell self-renewal.

    J Lipid Res 2010, 51:2082-2089. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  47. Park JH, Ryu JM, Han HJ: Involvement of caveolin-1 in fibronectin-induced mouse embryonic stem cell proliferation: role of FAK, RhoA, PI3K/Akt, and ERK 1/2 pathways.

    J Cell Physiol 2011, 226:267-275. PubMed Abstract | Publisher Full Text OpenURL

  48. Park JH, Lee MY, Han HJ: A potential role for caveolin-1 in estradiol-17β-induced proliferation of mouse embryonic stem cells: involvement of Src, PI3K/Akt, and MAPKs pathways.

    Int J Biochem Cell Biol 2009, 41:659-665. PubMed Abstract | Publisher Full Text OpenURL

  49. Park JH, Han HJ: Caveolin-1 plays important role in EGF-induced migration and proliferation of mouse embryonic stem cells: involvement of PI3K/Akt and ERK.

    Am J Physiol Cell Physiol 2009, 297:C935-C944. PubMed Abstract | Publisher Full Text OpenURL

  50. Galbiati F, Volonte D, Brown AM, Weinstein DE, Ben-Ze'ev A, Pestell RG, Lisanti MP: Caveolin-1 expression inhibits Wnt/beta-catenin/Lef-1 signaling by recruiting beta-catenin to caveolae membrane domains.

    J Biol Chem 2000, 275:23368-23377. PubMed Abstract | Publisher Full Text OpenURL

  51. Lu Z, Ghosh S, Wang Z, Hunter T: Downregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasion.

    Cancer Cell 2003, 4:499-515. PubMed Abstract | Publisher Full Text OpenURL

  52. Torres VA, Tapia JC, Rodriguez DA, Lladser A, Arredondo C, Leyton L, Quest AF: E-cadherin is required for caveolin-1-mediated down-regulation of the inhibitor of apoptosis protein survivin via reduced beta-catenin-Tcf/Lef-dependent transcription.

    Mol Cell Biol 2007, 27:7703-7717. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  53. Rodriguez DA, Tapia JC, Fernandez JG, Torres VA, Munoz N, Galleguillos D, Leyton L, Quest AF: Caveolin-1-mediated suppression of cyclooxygenase-2 via a beta-catenin-Tcf/Lef-dependent transcriptional mechanism reduced prostaglandin E2 production and survivin expression.

    Mol Biol Cell 2009, 20:2297-2310. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  54. Mo S, Wang L, Li Q, Li J, Li Y, Thannickal VJ, Cui Z: Caveolin-1 regulates dorsoventral patterning through direct interaction with beta-catenin in zebrafish.

    Dev Biol 2010, 344:210-223. PubMed Abstract | Publisher Full Text OpenURL

  55. Razani B, Zhang XL, Bitzer M, von Gersdorff G, Bottinger EP, Lisanti MP: Caveolin-1 regulates transforming growth factor (TGF)-beta/SMAD signaling through an interaction with the TGF-beta type I receptor.

    J Biol Chem 2001, 276:6727-6738. PubMed Abstract | Publisher Full Text OpenURL

  56. Chen YG: Endocytic regulation of TGF-beta signaling.

    Cell Res 2009, 19:58-70. PubMed Abstract | Publisher Full Text OpenURL

  57. Del Galdo F, Lisanti MP, Jimenez SA: Caveolin-1, transforming growth factor-beta receptor internalization, and the pathogenesis of systemic sclerosis.

    Curr Opin Rheumatol 2008, 20:713-719. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  58. Kim S, Lee Y, Seo JE, Cho KH, Chung JH: Caveolin-1 increases basal and TGF-β1-induced expression of type I procollagen through PI-3 kinase/Akt/mTOR pathway in human dermal fibroblasts.

    Cell Signal 2008, 20:1313-1319. PubMed Abstract | Publisher Full Text OpenURL

  59. Santibanez JF, Blanco FJ, Garrido-Martin EM, Sanz-Rodriguez F, del Pozo MA, Bernabeu C: Caveolin-1 interacts and cooperates with the transforming growth factor-beta type I receptor ALK1 in endothelial caveolae.

    Cardiovasc Res 2008, 77:791-799. PubMed Abstract | Publisher Full Text OpenURL

  60. Lee EK, Lee YS, Han IO, Park SH: Expression of caveolin-1 reduces cellular responses to TGF-β1 through down-regulating the expression of TGF-β type II receptor gene in NIH3T3 fibroblast cells.

    Biochem Biophys Res Commun 2007, 359:385-390. PubMed Abstract | Publisher Full Text OpenURL

  61. Meyer C, Godoy P, Bachmann A, Liu Y, Barzan D, Ilkavets I, Maier P, Herskind C, Hengstler JG, Dooley S: Distinct role of endocytosis for Smad and non-Smad TGF-beta signaling regulation in hepatocytes.

    J Hepatol 2011, 55:369-378. PubMed Abstract | Publisher Full Text OpenURL

  62. Peng F, Zhang B, Wu D, Ingram AJ, Gao B, Krepinsky JC: TGFβ-induced RhoA activation and fibronectin production in mesangial cells require caveolae.

    Am J Physiol Renal Physiol 2008, 295:F153-F164. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  63. Nohe A, Keating E, Underhill TM, Knaus P, Petersen NO: Dynamics and interaction of caveolin-1 isoforms with BMP-receptors.

    J Cell Sci 2005, 118:643-650. PubMed Abstract | Publisher Full Text OpenURL

  64. Hartung A, Bitton-Worms K, Rechtman MM, Wenzel V, Boergermann JH, Hassel S, Henis YI, Knaus P: Different routes of bone morphogenic protein (BMP) receptor endocytosis influence BMP signaling.

    Mol Cell Biol 2006, 26:7791-7805. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  65. Wertz JW, Bauer PM: Caveolin-1 regulates BMPRII localization and signaling in vascular smooth muscle cells.

    Biochem Biophys Res Commun 2008, 375:557-561. PubMed Abstract | Publisher Full Text OpenURL

  66. Bonor J, Adams EL, Bragdon B, Moseychuk O, Czymmek KJ, Nohe A: Initiation of BMP2 signaling in domains on the plasma membrane.

    J Cell Physiol 2012, 227:2880-2888. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  67. Nohe A, Keating E, Loh C, Underhill MT, Petersen NO: Caveolin-1 isoform reorganization studied by image correlation spectroscopy.

    Faraday Discuss 2004, 126:185-195.

    discussion 245–254

    PubMed Abstract OpenURL

  68. Matveev S, van der Westhuyzen DR, Smart EJ: Co-expression of scavenger receptor-BI and caveolin-1 is associated with enhanced selective cholesteryl ester uptake in THP-1 macrophages.

    J Lipid Res 1999, 40:1647-1654. PubMed Abstract | Publisher Full Text OpenURL

  69. Ng YS, Ramsauer M, Loureiro RM, D'Amore PA: Identification of genes involved in VEGF-mediated vascular morphogenesis using embryonic stem cell-derived cystic embryoid bodies.

    Lab Invest 2004, 84:1209-1218. PubMed Abstract | Publisher Full Text OpenURL

  70. Liu J, Wang XB, Park DS, Lisanti MP: Caveolin-1 expression enhances endothelial capillary tubule formation.

    J Biol Chem 2002, 277:10661-10668. PubMed Abstract | Publisher Full Text OpenURL

  71. Campbell L, Hollins AJ, Al-Eid A, Newman GR, von Ruhland C, Gumbleton M: Caveolin-1 expression and caveolae biogenesis during cell transdifferentiation in lung alveolar epithelial primary cultures.

    Biochem Biophys Res Commun 1999, 262:744-751. PubMed Abstract | Publisher Full Text OpenURL

  72. Fuchs S, Hollins AJ, Laue M, Schaefer UF, Roemer K, Gumbleton M, Lehr CM: Differentiation of human alveolar epithelial cells in primary culture: morphological characterization and synthesis of caveolin-1 and surfactant protein-C.

    Cell Tissue Res 2003, 311:31-45. PubMed Abstract | Publisher Full Text OpenURL

  73. Wang S, Kan Q, Sun Y, Han R, Zhang G, Peng T, Jia Y: Caveolin-1 regulates neural differentiation of rat bone mesenchymal stem cells into neurons by modulating Notch signaling.

    Int J Dev Neurosci 2013, 31:30-35. PubMed Abstract | Publisher Full Text OpenURL

  74. Rubin J, Schwartz Z, Boyan BD, Fan X, Case N, Sen B, Drab M, Smith D, Aleman M, Wong KL, Yao H, Jo H, Gross TS: Caveolin-1 knockout mice have increased bone size and stiffness.

    J Bone Miner Res 2007, 22:1408-1418. PubMed Abstract | Publisher Full Text OpenURL

  75. Li Y, Lau WM, So KF, Tong Y, Shen J: Caveolin-1 inhibits oligodendroglial differentiation of neural stem/progenitor cells through modulating beta-catenin expression.

    Neurochem Int 2011, 59:114-121. PubMed Abstract | Publisher Full Text OpenURL

  76. Li Y, Luo J, Lau WM, Zheng G, Fu S, Wang TT, Zeng HP, So KF, Chung SK, Tong Y, Liu K, Shen J: Caveolin-1 plays a crucial role in inhibiting neuronal differentiation of neural stem/progenitor cells via VEGF signaling-dependent pathway.

    PLoS One 2011, 6:e22901. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  77. Kha HT, Basseri B, Shouhed D, Richardson J, Tetradis S, Hahn TJ, Parhami F: Oxysterols regulate differentiation of mesenchymal stem cells: pro-bone and anti-fat.

    J Bone Miner Res 2004, 19:830-840. PubMed Abstract | Publisher Full Text OpenURL

  78. Song C, Guo Z, Ma Q, Chen Z, Liu Z, Jia H, Dang G: Simvastatin induces osteoblastic differentiation and inhibits adipocytic differentiation in mouse bone marrow stromal cells.

    Biochem Biophys Res Commun 2003, 308:458-462. PubMed Abstract | Publisher Full Text OpenURL

  79. Baek KH, Lee WY, Oh KW, Tae HJ, Lee JM, Lee EJ, Han JH, Kang MI, Cha BY, Lee KW, Son HY, Kang SK: The effect of simvastatin on the proliferation and differentiation of human bone marrow stromal cells.

    J Korean Med Sci 2005, 20:438-444. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  80. Fielding CJ, Bist A, Fielding PE: Caveolin mRNA levels are up-regulated by free cholesterol and down-regulated by oxysterols in fibroblast monolayers.

    Proc Natl Acad Sci USA 1997, 94:3753-3758. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  81. Smart EJ, Ying YS, Conrad PA, Anderson RG: Caveolin moves from caveolae to the Golgi apparatus in response to cholesterol oxidation.

    J Cell Biol 1994, 127:1185-1197. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  82. Bragdon B, D'Angelo A, Gurski L, Bonor J, Schultz KL, Beamer WG, Rosen CJ, Nohe A: Altered plasma membrane dynamics of bone morphogenetic protein receptor type Ia in a low bone mass mouse model.

    Bone 2012, 50:189-199. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  83. Bragdon B, Bonor J, Shultz KL, Beamer WG, Rosen CJ, Nohe A: Bone morphogenetic protein receptor type Ia localization causes increased BMP2 signaling in mice exhibiting increased peak bone mass phenotype.

    J Cell Physiol 2012, 227:2870-2879. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  84. Du J, Chen X, Liang X, Zhang G, Xu J, He L, Zhan Q, Feng XQ, Chien S, Yang C: Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity.

    Proc Natl Acad Sci USA 2011, 108:9466-9471. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  85. Engler AJ, Sen S, Sweeney HL, Discher DE: Matrix elasticity directs stem cell lineage specification.

    Cell 2006, 126:677-689. PubMed Abstract | Publisher Full Text OpenURL

  86. Gilbert PM, Havenstrite KL, Magnusson KE, Sacco A, Leonardi NA, Kraft P, Nguyen NK, Thrun S, Lutolf MP, Blau HM: Substrate elasticity regulates skeletal muscle stem cell self-renewal in culture.

    Science 2010, 329:1078-1081. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  87. Li Y, Lau WM, So KF, Tong Y, Shen J: Caveolin-1 promote astroglial differentiation of neural stem/progenitor cells through modulating Notch1/NICD and Hes1 expressions.

    Biochem Biophys Res Commun 2011, 407:517-524. PubMed Abstract | Publisher Full Text OpenURL

  88. Park DS, Lee H, Riedel C, Hulit J, Scherer PE, Pestell RG, Lisanti MP: Prolactin negatively regulates caveolin-1 gene expression in the mammary gland during lactation, via a Ras-dependent mechanism.

    J Biol Chem 2001, 276:48389-48397. PubMed Abstract | Publisher Full Text OpenURL

  89. Park DS, Lee H, Frank PG, Razani B, Nguyen AV, Parlow AF, Russell RG, Hulit J, Pestell RG, Lisanti MP: Caveolin-1-deficient mice show accelerated mammary gland development during pregnancy, premature lactation, and hyperactivation of the Jak-2/STAT5a signaling cascade.

    Mol Biol Cell 2002, 13:3416-3430. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  90. Volonte D, Liu Y, Galbiati F: The modulation of caveolin-1 expression controls satellite cell activation during muscle repair.

    FASEB J 2005, 19:237-239. PubMed Abstract | Publisher Full Text OpenURL

  91. Rhim JH, Kim JH, Yeo EJ, Kim JC, Park SC: Caveolin-1 as a novel indicator of wound-healing capacity in aged human corneal epithelium.

    Mol Med 2010, 16:527-534. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  92. Mikol DD, Scherer SS, Duckett SJ, Hong HL, Feldman EL: Schwann cell caveolin-1 expression increases during myelination and decreases after axotomy.

    Glia 2002, 38:191-199. PubMed Abstract | Publisher Full Text OpenURL

  93. Miyasato SK, Loeffler J, Shohet R, Zhang J, Lindsey M, Le Saux CJ: Caveolin-1 modulates TGF-beta1 signaling in cardiac remodeling.

    Matrix Biol 2011, 30:318-329. PubMed Abstract | Publisher Full Text OpenURL

  94. Ratajczak P, Damy T, Heymes C, Oliviero P, Marotte F, Robidel E, Sercombe R, Boczkowski J, Rappaport L, Samuel JL: Caveolin-1 and −3 dissociations from caveolae to cytosol in the heart during aging and after myocardial infarction in rat.

    Cardiovasc Res 2003, 57:358-369. PubMed Abstract | Publisher Full Text OpenURL

  95. Young LH, Ikeda Y, Lefer AM: Caveolin-1 peptide exerts cardioprotective effects in myocardial ischemia–reperfusion via nitric oxide mechanism.

    Am J Physiol Heart Circ Physiol 2001, 280:H2489-H2495. PubMed Abstract | Publisher Full Text OpenURL

  96. Woodman SE, Ashton AW, Schubert W, Lee H, Williams TM, Medina FA, Wyckoff JB, Combs TP, Lisanti MP: Caveolin-1 knockout mice show an impaired angiogenic response to exogenous stimuli.

    Am J Pathol 2003, 162:2059-2068. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  97. Milovanova T, Chatterjee S, Hawkins BJ, Hong N, Sorokina EM, Debolt K, Moore JS, Madesh M, Fisher AB: Caveolae are an essential component of the pathway for endothelial cell signaling associated with abrupt reduction of shear stress.

    Biochim Biophys Acta 2008, 1783:1866-1875. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  98. Sonveaux P, Martinive P, DeWever J, Batova Z, Daneau G, Pelat M, Ghisdal P, Gregoire V, Dessy C, Balligand JL, Feron O: Caveolin-1 expression is critical for vascular endothelial growth factor-induced ischemic hindlimb collateralization and nitric oxide-mediated angiogenesis.

    Circ Res 2004, 95:154-161. PubMed Abstract | Publisher Full Text OpenURL

  99. Jasmin JF, Malhotra S, Singh Dhallu M, Mercier I, Rosenbaum DM, Lisanti MP: Caveolin-1 deficiency increases cerebral ischemic injury.

    Circ Res 2007, 100:721-729. PubMed Abstract | Publisher Full Text OpenURL

  100. Fernandez MA, Albor C, Ingelmo-Torres M, Nixon SJ, Ferguson C, Kurzchalia T, Tebar F, Enrich C, Parton RG, Pol A: Caveolin-1 is essential for liver regeneration.

    Science 2006, 313:1628-1632. PubMed Abstract | Publisher Full Text OpenURL

  101. Mayoral R, Fernandez-Martinez A, Roy R, Bosca L, Martin-Sanz P: Dispensability and dynamics of caveolin-1 during liver regeneration and in isolated hepatic cells.

    Hepatology 2007, 46:813-822. PubMed Abstract | Publisher Full Text OpenURL

  102. Mayoral R, Valverde AM, Llorente Izquierdo C, Gonzalez-Rodriguez A, Bosca L, Martin-Sanz P: Impairment of transforming growth factor beta signaling in caveolin-1-deficient hepatocytes: role in liver regeneration.

    J Biol Chem 2010, 285:3633-3642. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  103. Fujigaki Y, Sakakima M, Sun Y, Goto T, Ohashi N, Fukasawa H, Tsuji T, Yamamoto T, Hishida A: Immunohistochemical study on caveolin-1α in regenerating process of tubular cells in gentamicin-induced acute tubular injury in rats.

    Virchows Arch 2007, 450:671-681. PubMed Abstract | Publisher Full Text OpenURL

  104. Bass MD, Williamson RC, Nunan RD, Humphries JD, Byron A, Morgan MR, Martin P, Humphries MJ: A syndecan-4 hair trigger initiates wound healing through caveolin- and RhoG-regulated integrin endocytosis.

    Dev Cell 2011, 21:681-693. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  105. Grande-Garcia A, Echarri A, de Rooij J, Alderson NB, Waterman-Storer CM, Valdivielso JM, del Pozo MA: Caveolin-1 regulates cell polarization and directional migration through Src kinase and Rho GTPases.

    J Cell Biol 2007, 177:683-694. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  106. Roelandt T, Giddelo C, Heughebaert C, Denecker G, Hupe M, Crumrine D, Kusuma A, Haftek M, Roseeuw D, Declercq W, Feingold KR, Elias PM, Hachem JP: The ‘caveolae brake hypothesis’ and the epidermal barrier.

    J Invest Dermatol 2009, 129:927-936. PubMed Abstract | Publisher Full Text OpenURL

  107. Grande-Garcia A, del Pozo MA: Caveolin-1 in cell polarization and directional migration.

    Eur J Cell Biol 2008, 87:641-647. PubMed Abstract | Publisher Full Text OpenURL

  108. Park JH, Ryu JM, Yun SP, Kim MO, Han HJ: Fibronectin stimulates migration through lipid raft dependent NHE-1 activation in mouse embryonic stem cells: involvement of RhoA, Ca2+/CaM, and ERK.

    Biochim Biophys Acta 1820, 2012:1618-1627. OpenURL

  109. Ratliff BB, Singh N, Yasuda K, Park HC, Addabbo F, Ghaly T, Rajdev M, Jasmin JF, Plotkin M, Lisanti MP, Goligorsky MS: Mesenchymal stem cells, used as bait, disclose tissue binding sites: a tool in the search for the niche?

    Am J Pathol 2010, 177:873-883. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  110. Wysoczynski M, Reca R, Ratajczak J, Kucia M, Shirvaikar N, Honczarenko M, Mills M, Wanzeck J, Janowska-Wieczorek A, Ratajczak MZ: Incorporation of CXCR4 into membrane lipid rafts primes homing-related responses of hematopoietic stem/progenitor cells to an SDF-1 gradient.

    Blood 2005, 105:40-48. PubMed Abstract | Publisher Full Text OpenURL

  111. Sbaa E, Dewever J, Martinive P, Bouzin C, Frerart F, Balligand JL, Dessy C, Feron O: Caveolin plays a central role in endothelial progenitor cell mobilization and homing in SDF-1-driven postischemic vasculogenesis.

    Circ Res 2006, 98:1219-1227. PubMed Abstract | Publisher Full Text OpenURL

  112. Golden TR, Hinerfeld DA, Melov S: Oxidative stress and aging: beyond correlation.

    Aging Cell 2002, 1:117-123. PubMed Abstract | Publisher Full Text OpenURL

  113. Bosch M, Mari M, Herms A, Fernandez A, Fajardo A, Kassan A, Giralt A, Colell A, Balgoma D, Barbero E, Gonzalez-Moreno E, Matias N, Tebar F, Balsinde J, Camps M, Enrich C, Gross SP, Garcia-Ruiz C, Perez-Navarro E, Fernandez-Checa JC, Pol A: Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility.

    Curr Biol 2011, 21:681-686. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  114. Head BP, Peart JN, Panneerselvam M, Yokoyama T, Pearn ML, Niesman IR, Bonds JA, Schilling JM, Miyanohara A, Headrick J, Ali SS, Roth DM, Patel PM, Patel HH: Loss of caveolin-1 accelerates neurodegeneration and aging.

    PLoS One 2010, 5:e15697. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  115. Mercier I, Camacho J, Titchen K, Gonzales DM, Quann K, Bryant KG, Molchansky A, Milliman JN, Whitaker-Menezes D, Sotgia F, Jasmin JF, Schwarting R, Pestell RG, Blagosklonny MV, Lisanti MP: Caveolin-1 and accelerated host aging in the breast tumor microenvironment: chemoprevention with rapamycin, an mTOR inhibitor and anti-aging drug.

    Am J Pathol 2012, 181:278-293. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  116. Hekimi S, Lapointe J, Wen Y: Taking a ‘good’ look at free radicals in the aging process.

    Trends Cell Biol 2011, 21:569-576. PubMed Abstract | Publisher Full Text OpenURL

  117. Cohen AW, Combs TP, Scherer PE, Lisanti MP: Role of caveolin and caveolae in insulin signaling and diabetes.

    Am J Physiol Endocrinol Metab 2003, 285:E1151-E1160. PubMed Abstract | Publisher Full Text OpenURL

  118. Cohen AW, Razani B, Wang XB, Combs TP, Williams TM, Scherer PE, Lisanti MP: Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue.

    Am J Physiol Cell Physiol 2003, 285:C222-C235. PubMed Abstract | Publisher Full Text OpenURL

  119. Razani B, Combs TP, Wang XB, Frank PG, Park DS, Russell RG, Li M, Tang B, Jelicks LA, Scherer PE, Lisanti MP: Caveolin-1-deficient mice are lean, resistant to diet-induced obesity, and show hypertriglyceridemia with adipocyte abnormalities.

    J Biol Chem 2002, 277:8635-8647. PubMed Abstract | Publisher Full Text OpenURL

  120. Park WY, Park JS, Cho KA, Kim DI, Ko YG, Seo JS, Park SC: Up-regulation of caveolin attenuates epidermal growth factor signaling in senescent cells.

    J Biol Chem 2000, 275:20847-20852. PubMed Abstract | Publisher Full Text OpenURL

  121. Cho KA, Ryu SJ, Park JS, Jang IS, Ahn JS, Kim KT, Park SC: Senescent phenotype can be reversed by reduction of caveolin status.

    J Biol Chem 2003, 278:27789-27795. PubMed Abstract | Publisher Full Text OpenURL

  122. Villeda SA, Luo J, Mosher KI, Zou B, Britschgi M, Bieri G, Stan TM, Fainberg N, Ding Z, Eggel A, Lucin KM, Czirr E, Park JS, Couillard-Despres S, Aigner L, Li G, Peskind ER, Kaye JA, Quinn JF, Galasko DR, Xie XS, Rando TA, Wyss-Coray T: The ageing systemic milieu negatively regulates neurogenesis and cognitive function.

    Nature 2011, 477:90-94. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  123. Fontana L, Partridge L, Longo VD: Extending healthy life span – from yeast to humans.

    Science 2010, 328:321-326. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  124. Gyurus E, Kaposztas Z, Kahan BD: Sirolimus therapy predisposes to new-onset diabetes mellitus after renal transplantation: a long-term analysis of various treatment regimens.

    Transplant Proc 2011, 43:1583-1592. PubMed Abstract | Publisher Full Text OpenURL

  125. Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E, Miller RA: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice.

    Nature 2009, 460:392-395. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  126. Chen C, Liu Y, Zheng P: mTOR regulation and therapeutic rejuvenation of aging hematopoietic stem cells.

    Sci Signal 2009, 2:ra75. PubMed Abstract | Publisher Full Text OpenURL

  127. Conboy IM, Rando TA: Aging, stem cells and tissue regeneration: lessons from muscle.

    Cell Cycle 2005, 4:407-410. PubMed Abstract | Publisher Full Text OpenURL

  128. Conboy IM, Conboy MJ, Wagers AJ, Girma ER, Weissman IL, Rando TA: Rejuvenation of aged progenitor cells by exposure to a young systemic environment.

    Nature 2005, 433:760-764. PubMed Abstract | Publisher Full Text OpenURL

  129. Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA: Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis.

    Science 2007, 317:807-810. PubMed Abstract | Publisher Full Text OpenURL

  130. Hruza Z: Increase of cholesterol turnover of old rats connected by parabiosis with young rats.

    Exp Gerontol 1971, 6:103-107. PubMed Abstract | Publisher Full Text OpenURL

  131. Li D, Zhou J, Chowdhury F, Cheng J, Wang N, Wang F: Role of mechanical factors in fate decisions of stem cells.

    Regen Med 2011, 6:229-240. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  132. Song MJ, Brady-Kalnay SM, McBride SH, Phillips-Mason P, Dean D, Knothe Tate ML: Mapping the mechanome of live stem cells using a novel method to measure local strain fields in situ at the fluid–cell interface.

    PLoS One 2012, 7:e43601. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  133. Rizzo V, Sung A, Oh P, Schnitzer JE: Rapid mechanotransduction in situ at the luminal cell surface of vascular endothelium and its caveolae.

    J Biol Chem 1998, 273:26323-26329. PubMed Abstract | Publisher Full Text OpenURL

  134. Sedding DG, Hermsen J, Seay U, Eickelberg O, Kummer W, Schwencke C, Strasser RH, Tillmanns H, Braun-Dullaeus RC: Caveolin-1 facilitates mechanosensitive protein kinase B (Akt) signaling in vitro and in vivo.

    Circ Res 2005, 96:635-642. PubMed Abstract | Publisher Full Text OpenURL

  135. Yu J, Bergaya S, Murata T, Alp IF, Bauer MP, Lin MI, Drab M, Kurzchalia TV, Stan RV, Sessa WC: Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels.

    J Clin Invest 2006, 116:1284-1291. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  136. Yang B, Radel C, Hughes D, Kelemen S, Rizzo V: p190 RhoGTPase-activating protein links the β1 integrin/caveolin-1 mechanosignaling complex to RhoA and actin remodeling.

    Arterioscler Thromb Vasc Biol 2011, 31:376-383. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  137. Radel C, Rizzo V: Integrin mechanotransduction stimulates caveolin-1 phosphorylation and recruitment of Csk to mediate actin reorganization.

    Am J Physiol Heart Circ Physiol 2005, 288:H936-H945. PubMed Abstract | Publisher Full Text OpenURL

  138. Radel C, Carlile-Klusacek M, Rizzo V: Participation of caveolae in beta1 integrin-mediated mechanotransduction.

    Biochem Biophys Res Commun 2007, 358:626-631. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  139. Kawabe J, Okumura S, Lee MC, Sadoshima J, Ishikawa Y: Translocation of caveolin regulates stretch-induced ERK activity in vascular smooth muscle cells.

    Am J Physiol Heart Circ Physiol 2004, 286:H1845-H1852. PubMed Abstract | Publisher Full Text OpenURL

  140. Kawamura S, Miyamoto S, Brown JH: Initiation and transduction of stretch-induced RhoA and Rac1 activation through caveolae: cytoskeletal regulation of ERK translocation.

    J Biol Chem 2003, 278:31111-31117. PubMed Abstract | Publisher Full Text OpenURL

  141. Zhang B, Peng F, Wu D, Ingram AJ, Gao B, Krepinsky JC: Caveolin-1 phosphorylation is required for stretch-induced EGFR and Akt activation in mesangial cells.

    Cell Signal 2007, 19:1690-1700. PubMed Abstract | Publisher Full Text OpenURL

  142. Peng F, Wu D, Ingram AJ, Zhang B, Gao B, Krepinsky JC: RhoA activation in mesangial cells by mechanical strain depends on caveolae and caveolin-1 interaction.

    J Am Soc Nephrol 2007, 18:189-198. PubMed Abstract | Publisher Full Text OpenURL

  143. Plotkin LI, Mathov I, Aguirre JI, Parfitt AM, Manolagas SC, Bellido T: Mechanical stimulation prevents osteocyte apoptosis: requirement of integrins, Src kinases, and ERKs.

    Am J Physiol Cell Physiol 2005, 289:C633-C643. PubMed Abstract | Publisher Full Text OpenURL

  144. Ferraro JT, Daneshmand M, Bizios R, Rizzo V: Depletion of plasma membrane cholesterol dampens hydrostatic pressure and shear stress-induced mechanotransduction pathways in osteoblast cultures.

    Am J Physiol Cell Physiol 2004, 286:C831-C839. PubMed Abstract | Publisher Full Text OpenURL

  145. Kozera L, White E, Calaghan S: Caveolae act as membrane reserves which limit mechanosensitive I(Cl, swell) channel activation during swelling in the rat ventricular myocyte.

    PLoS One 2009, 4:e8312. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL

  146. Kohl P, Cooper PJ, Holloway H: Effects of acute ventricular volume manipulation on in situ cardiomyocyte cell membrane configuration.

    Prog Biophys Mol Biol 2003, 82:221-227. PubMed Abstract | Publisher Full Text OpenURL

  147. Sinha B, Koster D, Ruez R, Gonnord P, Bastiani M, Abankwa D, Stan RV, Butler-Browne G, Vedie B, Johannes L, Morone N, Parton RG, Raposo G, Sens P, Lamaze C, Nassoy P: Cells respond to mechanical stress by rapid disassembly of caveolae.

    Cell 2011, 144:402-413. PubMed Abstract | Publisher Full Text | PubMed Central Full Text OpenURL