Project 4 will address the central PPG hypothesis that ACTA2 and MYH11 mutations decrease force generation by SMCs and lead to thoracic aneurysms in the aorta and occlusive vascular diseases in smaller arteries through activation of different and distinct pathways. Genetically modified mouse models of ACTA2 and MYH11 mutations identified in familial thoracic aortic disease will be characterized for thoracic aortic aneurysm formation and neointimal formation with vascular injury, and the proliferation of explanted aortic smooth muscle cells (SMCs) determined. Project 4 will characterize the tissue and cellular alterations related to the aneurysm progression and neointimal formation in vivo, along with assessing pathway leading to SMC proliferation in vitro. Finally, we will continue to identify genotypes and correlating phenotypes of patients with ACTA2 and MYH11 genetic variants to delineate the full range of genotypes, the associated phenotypes and begin to delineate the associated vascular disease risk.

Public Health Relevance

This study will identify the cell signaling, growth factors and cytokines, and proteases that lead to thoracic aortic aneurysms and dissections in a mouse model of the disease. Additionally, these studies will identify the pathways leading to increased neointimal formation associated with mutations in ACTA2.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Program Project Review Committee (HLBP)
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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
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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
Guo, Dong-Chuan; Hostetler, Ellen M; Fan, Yuxin et al. (2017) Heritable Thoracic Aortic Disease Genes in Sporadic Aortic Dissection. J Am Coll Cardiol 70:2728-2730
Ren, Pingping; Hughes, Michael; Krishnamoorthy, Swapna et al. (2017) Critical Role of ADAMTS-4 in the Development of Sporadic Aortic Aneurysm and Dissection in Mice. Sci Rep 7:12351
Liu, Zhenan; Chang, Audrey N; Grinnell, Frederick et al. (2017) Vascular disease-causing mutation, smooth muscle ?-actin R258C, dominantly suppresses functions of ?-actin in human patient fibroblasts. Proc Natl Acad Sci U S A 114:E5569-E5578

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