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)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
Project #
Application #
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Tolunay, Eser
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas Health Science Center Houston
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Karimi, Ashkan; Milewicz, Dianna M (2016) Structure of the Elastin-Contractile Units in the Thoracic Aorta and How Genes That Cause Thoracic Aortic Aneurysms and Dissections Disrupt This Structure. Can J Cardiol 32:26-34
Wallace, S; Guo, D-C; Regalado, E et al. (2016) Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension. Clin Genet 90:351-60
Guo, Dong-chuan; Regalado, Ellen S; Gong, Limin et al. (2016) LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections. Circ Res 118:928-34
Jondeau, Guillaume; Ropers, Jacques; Regalado, Ellen et al. (2016) International Registry of Patients Carrying TGFBR1 or TGFBR2 Mutations: Results of the MAC (Montalcino Aortic Consortium). Circ Cardiovasc Genet 9:548-558
Milewicz, Dianna; Hostetler, Ellen; Wallace, Stephanie et al. (2016) Precision medical and surgical management for thoracic aortic aneurysms and acute aortic dissections based on the causative mutant gene. J Cardiovasc Surg (Torino) 57:172-7
Abrams, Joshua; Einhorn, Zev; Seiler, Christoph et al. (2016) Graded effects of unregulated smooth muscle myosin on intestinal architecture, intestinal motility and vascular function in zebrafish. Dis Model Mech 9:529-40
Kuang, Shao-Qing; Medina-Martinez, Olga; Guo, Dong-Chuan et al. (2016) FOXE3 mutations predispose to thoracic aortic aneurysms and dissections. J Clin Invest 126:948-61
Chang, Audrey N; Kamm, Kristine E; Stull, James T (2016) Role of myosin light chain phosphatase in cardiac physiology and pathophysiology. J Mol Cell Cardiol 101:35-43
Ropars, Virginie; Yang, Zhaohui; Isabet, Tatiana et al. (2016) The myosin X motor is optimized for movement on actin bundles. Nat Commun 7:12456
Regalado, E S; Guo, D C; Santos-Cortez, R L P et al. (2016) Pathogenic FBN1 variants in familial thoracic aortic aneurysms and dissections. Clin Genet 89:719-23

Showing the most recent 10 out of 35 publications