Focal Adhesion Kinase Regulates Smooth Muscle Cell Recruitment to the Developing Vasculature

Cheng, Zhaokang; Sundberg-Smith, Liisa J.; Mangiante, Lee; Sayers, Rebecca L.; Hakim, Zeenat S.; Musunuri, Srilaxmi; Maguire, Colin T.; Majesky, Mark W.; Zhou, Zhigang; Mack, Christopher P.; Taylor, Joan M.

doi:10.1161/atvbaha.111.232231

Cited by 20 publications

(12 citation statements)

References 46 publications

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“…Focal adhesions are essential for maintaining structural integrity of vessels by inducing cytoskeletal rearrangements and alignment of vSMCs in response to mechanical strain. Previous studies have shown that genetic deletion of FAK (Ptk2) in vSMC precursors leads to defects in the patterning of the aortic arch arteries and septation of the heart and outflow tract (Hakim et al, 2007;Vallejo-Illarramendi et al, 2009;Cheng et al, 2011). These defects, however, are caused by abnormal recruitment (Hakim et al, 2007;Cheng et al, 2011) and/or impaired differentiation of vSMCs (Vallejo-Illarramendi et al, 2009), neither of which was seen in our mutants.…”

Section: Role Of α5 and αV Integrins In Cardiovascular Developmentcontrasting

confidence: 46%

α5 and αv integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo

et al. 2015

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The RGD-binding α5 and αv integrins have been shown to be key regulators of vascular smooth muscle cell (vSMC) function in vitro. However, their role on vSMCs during vascular development in vivo remains unclear. To address this issue, we have generated mice that lack α5, αv or both α5 and αv integrins on their vSMCs, using the SM22α-Cre transgenic mouse line. To our surprise, neither α5 nor αv mutants displayed any obvious vascular defects during embryonic development. By contrast, mice lacking both α5 and αv integrins developed interrupted aortic arches, large brachiocephalic/ carotid artery aneurysms and cardiac septation defects, but developed extensive and apparently normal vasculature in the skin. Cardiovascular defects were also found, along with cleft palates and ectopically located thymi, in Wnt1-Cre α5/αv mutants, suggesting that α5 and αv cooperate on neural crest-derived cells to control the remodelling of the pharyngeal arches and the septation of the heart and outflow tract. Analysis of cultured α5/αv-deficient vSMCs suggests that this is achieved, at least in part, through proper assembly of RGD-containing extracellular matrix proteins and the correct incorporation and activation of latent TGF-β.

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Section: Role Of α5 and αV Integrins In Cardiovascular Developmentcontrasting

confidence: 46%

α5 and αv integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo

et al. 2015

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“…Focal adhesion kinase has been reported to play a role in the proliferation and migration of aortic smooth muscle cells, and the regulation of smooth muscle cell recruitment during blood vessel morphogenesis . Myo1e has previously been reported to induce FAK phosphorylation and FAK kinase activity .…”

Section: Resultsmentioning

confidence: 99%

“…Heim et al reported that Myo1e binds to the FERM domain of focal adhesion kinase (FAK), activating FAK and inducing Y397 phosphorylation. Previous studies revealed that FAK is involved in the regulation of aortic smooth muscle cell motility and growth, and the regulation of smooth muscle cell recruitment during blood vessel morphogenesis . The potential role of Myo1e and FAK activation in VSMCs in response to MSC‐Exo‐derived signals was also investigated in this study.…”

Section: Introductionmentioning

confidence: 89%

Exosomes from mesenchymal stem cells expressing miR‐125b inhibit neointimal hyperplasia via myosin IE

Wang

Gao

Yue

et al. 2018

J Cellular Molecular Medi

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Intercellular communication between mesenchymal stem cells (MSCs) and their target cells in the perivascular environment is modulated by exosomes derived from MSCs. However, the potential role of exosome‐mediated microRNA transfer in neointimal hyperplasia remains to be investigated. To evaluate the effects of MSC‐derived exosomes (MSC‐Exo) on neointimal hyperplasia, their effects upon vascular smooth muscle cell (VSMC) growth in vitro and neointimal hyperplasia in vivo were assessed in a model of balloon‐induced vascular injury. Our results showed that MSC‐Exo were internalised by VSMCs and inhibited proliferation and migration in vitro. Further analysis revealed that miR‐125b was enriched in MSC‐Exo, and repressed the expression of myosin 1E (Myo1e) by targeting its 3ʹ untranslated region. Additionally, MSC‐Exo and exosomally transferred miR‐125b repressed Myo1e expression and suppressed VSMC proliferation and migration and neointimal hyperplasia in vivo. In summary, our findings revealed that MSC‐Exo can transfer miR‐125b to VSMCs and inhibit VSMC proliferation and migration in vitro and neointimal hyperplasia in vivo by repressing Myo1e, indicating that miR‐125b may be a therapeutic target in the treatment of vascular diseases.

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“…The inhibitory effect of SCARA5 on growth has been ascribed to the binding of FAK, which in turn inhibits downstream src-p130Cas activity 9 . In this regard, a study of smooth muscle cells reported that targeted knockout of FAK did not influence cell growth 12 , which appears to preclude a role for FAK in the inhibitory effect of SCARA5. However, Ojala et al reported that expression of SCARA5 in mice is limited to specific populations of fibroblasts in the interstitial space of most organs and is not found in smooth muscle alpha actin positive cells 7 .…”

Section: Discussionmentioning

confidence: 99%

Scavenger receptor class A member 5 ( SCARA5 ) and suprabasin ( SBSN ) are hub genes of coexpression network modules associated with peripheral vein graft patency

Kenagy

Civelek

Kikuchi

et al. 2016

Journal of Vascular Surgery

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Objective About 30% of autogenous vein grafts develop luminal narrowing and fail because of intimal hyperplasia or negative remodeling. We previously found that vein graft cells from patients that later develop stenosis proliferate more in vitro in response to growth factors than cells from patients that maintain patent grafts. To discover novel determinants of vein graft outcome we have analyzed gene expression profiles of these cells using a systems biology approach to cluster the genes into modules based on their co-expression patterns and to correlate the results with growth data from our prior study and with new studies of migration and matrix remodeling. Methods RNA from 4 hour serum- or PDGF-BB-stimulated human saphenous vein cells obtained from the outer vein wall (20 cell lines), was used for microarray analysis of gene expression followed by weighted gene co-expression network analysis. Cell migration in microchemotaxis chambers in response to PDGF-BB and cell-mediated collagen gel contraction in response to serum were also determined. Gene function was determined using siRNA to inhibit gene expression before subjecting cells to growth or collagen gel contraction assays. These cells were derived from samples of the vein grafts obtained at surgery, and the long term fate of these bypass grafts was known. Results Neither migration nor cell-mediated collagen gel contraction showed a correlation with graft outcome. While 1,188 and 1,340 genes were differentially expressed in response to treatment with serum and PDGF, respectively, no single gene was differentially expressed in cells isolated from patients whose grafts stenosed compared to those that remained patent. Network analysis revealed 4 unique groups of genes, which we term modules, associated with PDGF responses, and 20 unique modules associated with serum responses. The “Yellow” and “Skyblue” modules, from PDGF and serum analyses respectively, both correlated with later graft stenosis (P=.005 and .02, respectively). In response to PDGF, Yellow was also associated with increased cell growth. For serum, Skyblue was also associated with inhibition of collagen gel contraction. The hub genes for Yellow and Skyblue (i.e. the gene most connected to other genes in the module), SCARA5 and SBSN, respectively, were tested for effects on proliferation and collagen contraction. Knockdown of SCARA5 increased proliferation by 29.9 ± 7.8% (P<.01), while knockdown of SBSN had no effect. Knockdown of SBSN increased collagen gel contraction by 24.2 ± 8.6% (P<.05), while knockdown of SCARA5 had no effect. Conclusion Using weighted gene co-expression network analysis of cultured vein graft cell gene expression, we have discovered two small gene modules, which comprise 47 genes, that are associated with vein graft failure. Further experiments are needed to delineate the venous cells that express these genes in vivo and the roles these genes play in vein graft healing starting with the module hub genes SCARA5 and SBSN, which have been shown to have modest effects...

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Focal Adhesion Kinase Regulates Smooth Muscle Cell Recruitment to the Developing Vasculature

Cited by 20 publications

References 46 publications

α5 and αv integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo

α5 and αv integrins cooperate to regulate vascular smooth muscle and neural crest functions in vivo

Exosomes from mesenchymal stem cells expressing miR‐125b inhibit neointimal hyperplasia via myosin IE

Scavenger receptor class A member 5 ( SCARA5 ) and suprabasin ( SBSN ) are hub genes of coexpression network modules associated with peripheral vein graft patency

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