Smooth muscle hyperplasia due to loss of smooth muscle -actin is driven by activation of focal adhesion kinase, altered p53 localization and increased levels of platelet-derived growth factor receptor- (original) (raw)
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Proceedings of the National Academy of Sciences, 2017
The most common genetic alterations for familial thoracic aortic aneurysms and dissections (TAAD) are missense mutations in vascular smooth muscle (SM) α-actin encoded by ACTA2. We focus here on ACTA2–R258C, a recurrent mutation associated with early onset of TAAD and occlusive moyamoya-like cerebrovascular disease. Recent biochemical results with SM α-actin–R258C predicted that this variant will compromise multiple actin-dependent functions in intact cells and tissues, but a model system to measure R258C-induced effects was lacking. We describe the development of an approach to interrogate functional consequences of actin mutations in affected patient-derived cells. Primary dermal fibroblasts from R258C patients exhibited increased proliferative capacity compared with controls, consistent with inhibition of growth suppression attributed to SM α-actin. Telomerase-immortalized lines of control and R258C human dermal fibroblasts were established and SM α-actin expression induced with ...
Activin A induces a non-fibrotic phenotype in smooth muscle cells in contrast to TGF-β
Experimental Cell Research, 2011
Activin A and transforming growth factor-β1 (TGF-β1) belong to the same family of growth and differentiation factors that modulate vascular lesion formation in distinct ways, which we wish to understand mechanistically. Methods and results: We investigated the expression of cell-surface receptors and activation of Smads in human vascular smooth muscle cells (SMCs) and demonstrated that activin receptor-like kinase-1 (ALK-1), ALK-4, ALK-5 and endoglin are expressed in human SMCs. As expected, TGF-β1 activates Smad1 and Smad2 in these cells. Interestingly, activin A also induces phosphorylation of both Smads, which has not been reported for Smad1 before. Transcriptome analyses of activin A and TGF-β1 treated SMCs with subsequent Gene-Set Enrichment Analyses revealed that many downstream gene networks are induced by both factors. However, the effect of activin A on expression kinetics of individual genes is less pronounced than for TGF-β1, which is explained by a more rapid dephosphorylation of Smads and p38-MAPK in response to activin A. Substantial differences in expression of fibronectin, alpha-V integrin and total extracellular collagen synthesis were observed. Conclusions: Genome-wide mRNA expression analyses clarify the distinct modulation of vascular lesion formation by activin A and TGF-β1, most significantly because activin A is non-fibrotic.
The American Journal of Human Genetics, 2009
The vascular smooth muscle cell (SMC)-specific isoform of a-actin (ACTA2) is a major component of the contractile apparatus in SMCs located throughout the arterial system. Heterozygous ACTA2 mutations cause familial thoracic aortic aneurysms and dissections (TAAD), but only half of mutation carriers have aortic disease. Linkage analysis and association studies of individuals in 20 families with ACTA2 mutations indicate that mutation carriers can have a diversity of vascular diseases, including premature onset of coronary artery disease (CAD) and premature ischemic strokes (including Moyamoya disease [MMD]), as well as previously defined TAAD. Sequencing of DNA from patients with nonfamilial TAAD and from premature-onset CAD patients independently identified ACTA2 mutations in these patients and premature onset strokes in family members with ACTA2 mutations. Vascular pathology and analysis of explanted SMCs and myofibroblasts from patients harboring ACTA2 suggested that increased proliferation of SMCs contributed to occlusive diseases. These results indicate that heterozygous ACTA2 mutations predispose patients to a variety of diffuse and diverse vascular diseases, including TAAD, premature CAD, ischemic strokes, and MMD. These data demonstrate that diffuse vascular diseases resulting from either occluded or enlarged arteries can be caused by mutations in a single gene and have direct implications for clinical management and research on familial vascular diseases.
American Journal of Physiology-Heart and Circulatory Physiology, 2009
The objective of this study was to better understand the role of transforming growth factor-β (TGF-β) and its primary signaling protein Smad3 in the development of intimal hyperplasia. Male Sprague-Dawley rats underwent left carotid balloon injury followed by intra-arterial infection with adenovirus-expressing Smad3 (AdSmad3). In uninfected injured arteries, endogenous Smad3 was upregulated with the expression peaking at 14 days. Moreover, in arteries infected with AdSmad3, we observed an enhancement of intimal hyperplasia and increased vascular smooth muscle cell (VSMC) proliferation. The novel finding, that TGF-β/Smad3 stimulated rather than inhibited VSMC proliferation, was confirmed in cultured VSMCs infected with AdSmad3 and treated with TGF-β. To identify the mechanism underlying TGF-β/Smad3-mediated VSMC proliferation, we studied the cyclin-dependent kinase inhibitor p27. Although the upregulation of Smad3 in VSMCs had no significant effect on total p27 levels, Smad3 did stim...
Journal of Experimental Medicine, 2010
Members of the transforming growth factor β (TGF-β) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-β and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiological and pathological angiogenesis make the need for mechanistic studies apparent. We demonstrate, by genetic and pharmacological means, that the TGF-β and BMP9 receptor activin receptor-like kinase (ALK) 1 represents a new therapeutic target for tumor angiogenesis. Diminution of ALK1 gene dosage or systemic treatment with the ALK1-Fc fusion protein RAP-041 retarded tumor growth and progression by inhibition of angiogenesis in a transgenic mouse model of multistep tumorigenesis. Furthermore, RAP-041 significantly impaired the in vitro and in vivo angiogenic response toward vascular endothelial growth factor A and basic fibroblast growth factor. In seeking the mechanism for the observed ...
Experimental Cell Research, 1999
Activin A and Transforming Growth Factor- (TGF-) are members of a common family of cytokines that bind to and stimulate serine/threonine kinase receptors. Activin A and TGF- are important during embryonic development exerting both positive and negative effects on cell growth. In the adult organism, they function in processes such as tissue repair, cellular proliferation, and differentiation. Although activin A and TGF- often induce opposite functional outcomes in specific cells; proliferation or differentiation, both were found to stimulate the formation of actin stress fibers and focal adhesions in serum-starved rat aortic smooth muscle (RASM) cells. These structural changes were accompanied by phosphorylation of the focal adhesion proteins, paxillin, and p130 cas . Similar cytoskeletal and biochemical changes were observed with the vasoactive agonist angiotensin II. Activation of the ERK/MAP kinase pathway has been implicated in the migration in certain cell types. However, while activin A, TGF-, and angiotensin II all stimulated ERK activity in RASM cells, only activin A and angiotensin II stimulated migration. TGF- failed to illicit a chemotactic response. Furthermore, pharmacologic inhibition of MEK activity failed to block migration in response to activin A and angiotensin II, indicating RASM migration can occur independent of ERK activity. These results suggest that TGF- and activin A share several signaling pathways with angiotensin II leading to cytoskeletal remodeling and ERK activation, but there are distinct differences regarding the effect of these agonists on cellular migration.
Activin-like kinase receptor 1 (ALK1) in atherosclerotic lesions and vascular mesenchymal cells
Objective: Activin-like kinase receptor 1 (ALK1) is a transforming growth factor (TGF)-β type I receptor expressed in vascular mesenchyme, yet its function in vascular mesenchymal cells (VMC) is unclear. We examined ALK1 expression in human coronary atherosclerotic lesions and bovine and human VMC undergoing cellular condensation in vitro. We also examined the effect of activated ALK1 on cell proliferation and smooth muscle cell (SMC) differentiation. Methods and results: Our results showed that ALK1 was expressed in human coronary atherosclerotic lesions as determined by immunohistochemistry. ALK1 was also expressed in cellular condensations of bovine and human VMC as determined by real-time PCR and immunocytochemistry. Bone morphogenetic protein (BMP)-2, which is known to increase condensation size, increased ALK1 expression when induced from a BMP-2 adenoviral vector. In turn, activated ALK1 induced expression of matrix GLA protein (MGP), a BMP-2 inhibitor known to limit condensation size. Activated ALK1 enhanced proliferation of VMC as determined by 3 H-thymidine incorporation, whereas MGP decreased proliferation. Activated ALK1 also enhanced expression of SMC lineage markers and ALK5, another TGF-β type I receptor, as determined by immunoblotting, real-time PCR and immunocytochemistry. Anti-TGF-β antibodies abolished expression of SMC markers in the presence of constitutively active ALK1, suggesting that ALK1 activation alone is not sufficient to promote SMC differentiation. Conclusions: We conclude that there is a balance between the actions of BMP-2 and MGP in the initiation of vascular mesenchymal cell condensation and SMC differentiation, and that targeting ALK1, BMP2 and/or MGP may lead to novel concepts of atherosclerosis treatment.
E xcessive proliferation and migration of vascular smooth muscle cells (SMCs) contribute to occlusive cardiovascular diseases such as atherosclerosis. 1 Although SMCs in mature vessels have low proliferative and migratory activity, physical and inflammatory stimuli after vessel injury increases growth factor secretion and matrix synthesis, which promotes SMC proliferation and migration into the intima leading to arterial stenosis. 2-4 Current treatment strategies for stenotic atherosclerotic lesions include procedures, such as balloon angioplasty, stenting, or bypass vein graft surgery that restore blood flow through the atherosclerotic vessel. 5,6 Although these procedures are effective, they damage the artery and can lead to restenosis or reocclusion due to induction of SMC proliferation and migration. Drug-eluting stents and drug-coated balloons have been used to reduce restenosis, 7,8 but better treatment options are needed as size of the affected artery is still a major problem for intervention and prevention of restenosis. 9-11 Editorial, see p 167 In This Issue, see p 147 Meet the First Author, see p 148
Faseb Journal, 2006
itors p21 waf1 and p27 kip1 . Surprisingly, A20 sensitizes SMC to cytokine-and Fas-mediated apoptosis through a novel NO-dependent mechanism. In vivo, adenoviral delivery of A20 to medial rat carotid artery SMC after balloon angioplasty prevents neointimal hyperplasia by blocking SMC proliferation and accelerating re-endothelialization, without causing apoptosis. However, expression of A20 in established neointimal lesions leads to their regression through increased apoptosis. This is the first demonstration that A20 exerts two levels of control of vascular remodeling and healing. A20 prevents neointimal hyperplasia through combined antiinflammatory and antiproliferative functions in medial SMC. If SMC evade this first barrier and neointima is formed, A20 has a therapeutic potential by uniquely sensitizing neointimal SMC to apoptosis. A20-based therapies hold promise for the prevention and treatment of neointimal disease.-Patel, V. I., Daniel, S.,