Familial thoracic aortic aneurysms and dissection (TAAD) are linked to mutations in smooth muscle myosin heavy chain, actin and myosin light chain kinase (MLCK. We will test the overarching hypothesis that disease-causing mutations reduce smooth muscle contractile function.
Aim 1 : Test the hypothesis that MYH11 mutations that cause TAAD impair contractile output of smooth muscle cells. We will analyze aortic smooth muscle tissues from genetically modified mice for age-dependent adaptive changes in (1) expression of proteins in distinct adhiesion and contractile signaling modules, (2) [Ca2+]i and vasomotor performance in tissue rings in response to agonists, and (3) phosphorylation that activates the contractile myosin (RLC) or focal adhesion (paxillin) signaling modules.
Aim 2 : Test the hypothesis that heterozygous loss of MLCK activity impairs contractile output because of attenuated RLC phosphorylation in smooth muscle cells and leads to development of TAAD in the ascending aorta.
Aim 3 : Test the hypothesis that ACTA2 mutations that cause TAAD impair contractile output of smooth muscles. We will analyze the adhesion and contractile signaling modules as described in Aim 1 to determine if specific actin mutations promote selective dysfunction in one module or both.
Aim 4 : Test the hypothesis that ACTA2 mutations perturb myofibroblast contractions. MRTF-A will be used to induce myofibroblast phenotype expressing high amounts of smooth muscle a-actin in human dermal fibroblasts from patients harboring mutations in ACTA2. These studies will provide insights into the cellular basis of contractile performance defects associated with ACTA2 and MYH11 mutations examined at a molecular level in research Projects 1 and 2, and cellular pathways associated with reorganization of focal adhesions in mutant cells (Project 4). We also will continue collaborative studies on MLCK with Project 4.The synergy of our research interactions will provide an understanding of the molecular mechanisms that influence vascular disease based on the hypothesis that ACTA2, MYH11 and MYLK mutations lead to TAAD and occlusive vascular diseases due to selective dysfunctions of the contractile process.

Public Health Relevance

We plan to establish the quantitative importance specific proteins responsible for the contractile responses of smooth muscle cells in blood vessels in health which may be deranged with mutations associated with TAAD. Characterization of key signaling proteins will provide perspectives on clinical strategies for novel pharmacological targets to manage TAAD, and potentially on cellular adaptations that may contribute to derangement of contractile responses involving smooth muscle in other vascular diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL110869-03
Application #
8726464
Study Section
Heart, Lung, and Blood Program Project Review Committee (HLBP)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
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
Ijaz, Talha; Sun, Hong; Pinchuk, Irina V et al. (2017) Deletion of NF-?B/RelA in Angiotensin II-Sensitive Mesenchymal Cells Blocks Aortic Vascular Inflammation and Abdominal Aortic Aneurysm Formation. Arterioscler Thromb Vasc Biol 37:1881-1890
Chen, Jiyuan; Peters, Andrew; Papke, Christina L et al. (2017) Loss of Smooth Muscle ?-Actin Leads to NF-?B-Dependent Increased Sensitivity to Angiotensin II in Smooth Muscle Cells and Aortic Enlargement. Circ Res 120:1903-1915
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

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