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Contribution of endothelial dysfunction in progression of aortic aneurysm

Grant number: 18/15192-6
Support type:Regular Research Grants
Duration: December 01, 2018 - July 31, 2020
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Cooperation agreement: University of Tsukuba
Mobility Program: SPRINT - Projetos de pesquisa - Mobilidade
Principal Investigator:Rita de Cassia Aleixo Tostes Passaglia
Grantee:Rita de Cassia Aleixo Tostes Passaglia
Principal investigator abroad: Hiromi Yangisawa
Institution abroad: University of Tsukuba, Japan
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Associated research grant:13/08216-2 - CRID - Center for Research in Inflammatory Diseases, AP.CEPID

Abstract

Recent data from Prof. Hiromi Yangisawa's laboratory suggest that endothelial dysfunction may play an important role in progression of aortic aneurysms (unpublished data) and both teams have come to enter into collaboration with a goal to investigate the contribution of endothelial dysfunction in the progression of aortic aneurysm. Two aims were set to achieve this goal, as follows: 1) To characterize endothelial cells in aortic aneurysms in endothelial cell- and smooth muscle cell-specific double knockout mice (termed DKO) of fibulin-4, an extracellular matrix protein.2) To evaluate how oxidative stress and inflammation affects endothelial function in aortic aneurysms.During the course of our collaboration, we will utilize a mouse model of ascending aortic aneurysm established in Prof. Yanagisawa's laboratory and the DKO mice that develop much worse aneurysms involving both ascending and descending thoracic aortic segments. Based on the phenotypic comparison among single endothelial cell-specific, single smooth muscle cell-specific and DKO mice, we hypothesize that the absence of fibulin-4 in endothelial cells and in smooth muscle cells induces endothelial dysfunction, which affects communication between endothelial cells and smooth muscle cells. Dr. Tostes's team will provide the knowledge and expertise in evaluation of endothelial functions in vivo and in aortic samples. Dr. Yanagisawa's team will provide mouse aorta extracts to Dr. Tostes's team to evaluate oxidative stress and inflammatory markers, processes that can induce endothelial cells abnormalities. This project is particularly interesting and informative because in the aneurysm research field, it is generally thought that a weakness of aortic wall due to disruption of elastic fibers triggers the aneurysm formation. Therefore, the focus has been put on the investigation of smooth muscle cells rather than endothelial cells. In addition, abnormalities in the communication between endothelial cells and smooth muscle cells via gap junctions and exosomes in diseased aorta have been suggested. It will be particularly interesting to examine whether/how endothelial cells impact the progression of aortic aneurysms and whether oxidative stress and inflammation-related processes contribute to endothelial cells abnormalities in aortic aneurysms. (AU)