Vascular SMCs are arranged circumferentially in arteries in multiple layers, either embedded between layers of elastin lamellae in large elastic arteries or in a matrix of connective tissue in smaller muscular arteries. For contractile function, SMCs express smooth muscle specific isoforms of alpha-actin and Beta-myosin, which multimerize to form thin and thick filaments, respectively. We have determined that mutations in the genes encoding SMC alpha-actin and Beta-myosin, ACTA2 and MYH11, along with the kinase that controls SMC contraction, myosin light chain kinase (MYLK), predispose individuals to vascular diseases, including thoracic aortic aneurysms and aortic dissections and occlusive vascular diseases, such as early onset coronary artery disease and stroke. The Program Project Grant (PPG) will test the hypothesis that the ACTA2, MYH11 and MYLK mutations lead to thoracic aortic and disease and/or occlusive vascular diseases due to a differential SMC response to biomechanical stresses resulting from dysfunction of the contractile unit. We hypothesize that mutations in these genes cause a ?loss of function?, specifically loss of regulation or altered force output of contractile unit in SMCs in ascending aorta, resulting in increased biomechanical stresses and activation of SMC pathways leading to thoracic aortic aneurysms and aortic dissections. In contrast, we hypothesize that the occlusive vascular diseases associated with a subset of ACTA2 mutations, and possibly MYH11 variants, result from a SMC "gain of function" in muscular arteries, specifically increased SMC proliferation as a consequence of altered focal adhesions and activation of PDGFR-Beta receptors in response to abnormal cellular force generation. To test these hypotheses. Project 1 and 2 will assess the Impact of ACTA2 and MYH11 genetic variants on kinetics, motility, regulation, and filament formation in vitro. Project 3 will assess age-dependent derangements in specific signaling modules responsible for vasomotor responsiveness in vascular SMCs in mouse models of select ACTA2, MYH11 and MYLK mutations. Project 4 will Investigate SMC cellular pathways leading to thoracic aortic disease and SMC proliferation in these same mouse models.

Public Health Relevance

The proposed studies will provide insight into mechanisms leading to the vascular diseases due to disruption of contraction of the muscle cells that surround the arteries. These data may provide the basis for targeted therapeutics to prevent these vascular diseases, including thoracic aortic aneurysms and dissections, strokes and coronary artery disease.

National Institute of Health (NIH)
Research Program Projects (P01)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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Tolunay, Eser
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University of Texas Health Science Center Houston
Internal Medicine/Medicine
Schools of Medicine
United States
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Milewicz, Dianna M; Regalado, Ellen S; Shendure, Jay et al. (2014) Successes and challenges of using whole exome sequencing to identify novel genes underlying an inherited predisposition for thoracic aortic aneurysms and acute aortic dissections. Trends Cardiovasc Med 24:53-60
Kwartler, Callie S; Chen, Jiyuan; Thakur, Dhananjay et al. (2014) Overexpression of smooth muscle myosin heavy chain leads to activation of the unfolded protein response and autophagic turnover of thick filament-associated proteins in vascular smooth muscle cells. J Biol Chem 289:14075-88
Qiao, Yan-Ning; He, Wei-Qi; Chen, Cai-Ping et al. (2014) Myosin phosphatase target subunit 1 (MYPT1) regulates the contraction and relaxation of vascular smooth muscle and maintains blood pressure. J Biol Chem 289:22512-23
Regalado, Ellen S; Guo, Dong-chuan; Estrera, Anthony L et al. (2014) Acute aortic dissections with pregnancy in women with ACTA2 mutations. Am J Med Genet A 164A:106-12
Tsai, Ming-Ho; Chang, Audrey N; Huang, Jian et al. (2014) Constitutive phosphorylation of myosin phosphatase targeting subunit-1 in smooth muscle. J Physiol 592:3031-51
Nelson, Michael D; Rader, Florian; Tang, Xiu et al. (2014) PDE5 inhibition alleviates functional muscle ischemia in boys with Duchenne muscular dystrophy. Neurology 82:2085-91
Guo, Dong-chuan; Regalado, Ellen; Casteel, Darren E et al. (2013) Recurrent gain-of-function mutation in PRKG1 causes thoracic aortic aneurysms and acute aortic dissections. Am J Hum Genet 93:398-404
Gao, Ning; Huang, Jian; He, Weiqi et al. (2013) Signaling through myosin light chain kinase in smooth muscles. J Biol Chem 288:7596-605
Kuang, Shao-Qing; Geng, Liang; Prakash, Siddharth K et al. (2013) Aortic remodeling after transverse aortic constriction in mice is attenuated with AT1 receptor blockade. Arterioscler Thromb Vasc Biol 33:2172-9
Barua, Bipasha; Fagnant, Patricia M; Winkelmann, Donald A et al. (2013) A periodic pattern of evolutionarily conserved basic and acidic residues constitutes the binding interface of actin-tropomyosin. J Biol Chem 288:9602-9

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