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. .
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.
|Kim, Jungsil; Staiculescu, Marius Catalin; Cocciolone, Austin J et al. (2017) Crosslinked elastic fibers are necessary for low energy loss in the ascending aorta. J Biomech 61:199-207|
|Yamashiro, Yoshito; Papke, Christina L; Kim, Jungsil et al. (2015) Abnormal mechanosensing and cofilin activation promote the progression of ascending aortic aneurysms in mice. Sci Signal 8:ra105|
|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|
|Papke, Christina L; Tsunezumi, Jun; Ringuette, Léa-Jeanne et al. (2015) Loss of fibulin-4 disrupts collagen synthesis and maturation: implications for pathology resulting from EFEMP2 mutations. Hum Mol Genet 24:5867-79|
|Le, Victoria P; Cheng, Jeffrey K; Kim, Jungsil et al. (2015) Mechanical factors direct mouse aortic remodelling during early maturation. J R Soc Interface 12:20141350|
|Papke, Christina L; Yamashiro, Yoshito; Yanagisawa, Hiromi (2015) MMP17/MT4-MMP and thoracic aortic aneurysms: OPNing new potential for effective treatment. Circ Res 117:109-12|
|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|
|Gabriela Espinosa, M; Gardner, William S; Bennett, Lisa et al. (2014) The effects of elastic fiber protein insufficiency and treatment on the modulus of arterial smooth muscle cells. J Biomech Eng 136:021030|
|Papke, Christina L; Yanagisawa, Hiromi (2014) Fibulin-4 and fibulin-5 in elastogenesis and beyond: Insights from mouse and human studies. Matrix Biol 37:142-9|
|Budatha, Madhusudhan; Silva, Simone; Montoya, Teodoro Ignacio et al. (2013) Dysregulation of protease and protease inhibitors in a mouse model of human pelvic organ prolapse. PLoS One 8:e56376|
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