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 o-actin and (3-myosin, which multimerize to form thin and thick filaments, respectively. We have determined that mutations in the genes encoding SMC a-actin and p-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-P 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
3P01HL110869-04S1
Application #
9135112
Study Section
Program Officer
Tolunay, Eser
Project Start
2016-01-07
Project End
2017-07-31
Budget Start
2016-01-07
Budget End
2016-07-31
Support Year
4
Fiscal Year
2016
Total Cost
$49,793
Indirect Cost
$17,460
Name
University of Texas Health Science Center Houston
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
Shalata, Adel; Mahroom, Mohammad; Milewicz, Dianna M et al. (2018) Fatal thoracic aortic aneurysm and dissection in a large family with a novel MYLK gene mutation: delineation of the clinical phenotype. Orphanet J Rare Dis 13:41
Regalado, Ellen S; Mellor-Crummey, Lauren; De Backer, Julie et al. (2018) Clinical history and management recommendations of the smooth muscle dysfunction syndrome due to ACTA2 arginine 179 alterations. Genet Med 20:1206-1215
Lowey, Susan; Bretton, Vera; Joel, Peteranne B et al. (2018) Hypertrophic cardiomyopathy R403Q mutation in rabbit ?-myosin reduces contractile function at the molecular and myofibrillar levels. Proc Natl Acad Sci U S A 115:11238-11243
Robinet, Peggy; Milewicz, Dianna M; Cassis, Lisa A et al. (2018) Consideration of Sex Differences in Design and Reporting of Experimental Arterial Pathology Studies-Statement From ATVB Council. Arterioscler Thromb Vasc Biol 38:292-303
Kwartler, Callie S; Gong, Limin; Chen, Jiyuan et al. (2018) Variants of Unknown Significance in Genes Associated with Heritable Thoracic Aortic Disease Can Be Low Penetrant ""Risk Variants"". Am J Hum Genet 103:138-143
Tan, Kai Li; Haelterman, Nele A; Kwartler, Callie S et al. (2018) Ari-1 Regulates Myonuclear Organization Together with Parkin and Is Associated with Aortic Aneurysms. Dev Cell 45:226-244.e8
Guo, Dong-Chuan; Regalado, Ellen S; Pinard, Amelie et al. (2018) LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections. Am J Hum Genet 102:706-712
Milewicz, Dianna M; Prakash, Siddharth K; Ramirez, Francesco (2017) Therapeutics Targeting Drivers of Thoracic Aortic Aneurysms and Acute Aortic Dissections: Insights from Predisposing Genes and Mouse Models. Annu Rev Med 68:51-67
Humphrey, Jay D; Milewicz, Dianna M (2017) Aging, Smooth Muscle Vitality, and Aortic Integrity. Circ Res 120:1849-1851
Guo, Dong-Chuan; Duan, Xue-Yan; Regalado, Ellen S et al. (2017) Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease. Am J Hum Genet 100:21-30

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