Defects in synthesis/assembly of vascular extracellular matrix (ECM) or accelerated degradation of ECM are known causes of aortic aneurysms. ECM also serves as an external regulator of growth factor-mediated signaling by sequestering and fine-tuning the level of available ligands. In addition, ECM has profound effects on smooth muscle cell (SMC) phenotypes and mutations in SMC contractile proteins have been shown to be responsible for subsets of thoracic aortic aneurysms in humans. Fibulin-4 (Fbln4) is a secreted glycoprotein expressed in large blood vessels and essential for formation of elastic fibers in vivo. Fbln4 deficiency in mouse and humans results in cutis laxa and aortic aneurysms with severe disruption of elastic fibers. We recently generated mice carrying conditional knockout alleles of Fbln4 and showed that lack of Fbln4 in SMCs (Fbln4SMKO) leads to aortic aneurysms exclusively in the ascending aorta by 3-months of age. Fbln4SMKO aortae develop abnormal elastin and collagen fibers and a focal thickening of the aortic wall with proliferation of SMCs, downregulation of terminal SMC differentiation markers and a marked increase in phosphorylated (p-)ERK1/2 levels. In our preliminary studies, we show that the angiotensin II type 1 receptor (AT1R) blocker losartan effectively prevents aortic aneurysms with downregulation of p-ERK1/2 levels. This observation led us to hypothesize that fibulin-4 deficiency contributes to aneurysm formation through dysregulated angiotensin II (AngII) signaling in SMCs. In this application, we propose to investigate the underlying mechanism of AngII-AT1R activation in the vessel wall of Fbln4SMKO mice. We will address how altered ECM, SMC phenotype and AngII-AT1R signaling influence each other in the development of aortic aneurysms and how to obviate this process by pharmacological interventions. To test our hypothesis, our specific aims are as follows: 1) To determine if dysregulated Ang II- AT1R-mediated signaling plays a central role in aneurysm development in the Fbln4SMKO aorta, 2) To investigate the mechanism(s) of activation of Ang II-AT1R signaling pathway in Fbln4-deficient aorta, and 3) To investigate the mechanism by which abnormal SMCs and ECM contribute to aneurysm formation in Fbln4SMKO mice. Understanding the dynamic relationship between ECM and SMCs will provide a solid foundation for pharmacological interventions and could offer new therapeutic opportunities to various congenital aortic aneurysms. .

Public Health Relevance

This proposal focuses on a protein called fibulin-4 produced by vascular cells, which is essential for the development of a healthy vessel wall. We will study how this protein functions to prevent the development of aortic aneurysms.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
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Tolunay, Eser
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University of Texas Sw Medical Center Dallas
Schools of Medicine
United States
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Wagenseil, Jessica E (2018) Bio-chemo-mechanics of thoracic aortic aneurysms. Curr Opin Biomed Eng 5:50-57
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Yamashiro, Yoshito; Thang, Bui Quoc; Shin, Seung Jae et al. (2018) Role of Thrombospondin-1 in Mechanotransduction and Development of Thoracic Aortic Aneurysm in Mouse and Humans. Circ Res 123:660-672
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Kim, Jungsil; Procknow, Jesse D; Yanagisawa, Hiromi et al. (2015) Differences in genetic signaling, and not mechanical properties of the wall, are linked to ascending aortic aneurysms in fibulin-4 knockout mice. Am J Physiol Heart Circ Physiol 309:H103-13
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Le, Victoria P; Yamashiro, Yoshito; Yanagisawa, Hiromi et al. (2014) Measuring, reversing, and modeling the mechanical changes due to the absence of Fibulin-4 in mouse arteries. Biomech Model Mechanobiol 13:1081-95

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