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Redox mechanisms of angiogenesis: effect of protein disulfide isomerase (PDIA1) in a novel model of transgenic mouse

Grant number: 17/06192-0
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): November 01, 2017
Effective date (End): January 31, 2020
Field of knowledge:Biological Sciences - Physiology - Physiology of Organs and Systems
Principal researcher:Francisco Rafael Martins Laurindo
Grantee:Victor Eidi Koike Sakaguchi
Home Institution: Instituto do Coração Professor Euryclides de Jesus Zerbini (INCOR). Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil

Abstract

Angiogenesis is an important redox-modulated mechanism of disease, but pathways involved in this regulation are unclear. Protein Disulfide Isomerase (PDI or PDIA1) is an oxidoreductase of the thioredoxin superfamily, primarily of the endoplasmic reticulum (ER), having the main function of redox protein folding catalysis. Ongoing studies of our laboratory characterized an important role of PDIA1 on the regulation of the NADPH oxidase complex from the Nox family, the main enzymatic source of oxidant species with cell signaling function in vessels. In these studies, we identified that the induced overexpression of PDIA1 in smooth muscle cells promotes spontaneous activation of Nox1 NADPH oxidases and accelerates cell migration. Recently, our group developed a model of transgenic overexpression of PDIA1 in mice. This is a constitutive (i.e., not inducible) and ubiquitous (i.e., not organ-specific) overexpression. This model, developed entirely in Brazil, has potentially significant implications for the understanding of the role of PDIA1 in biological systems and pathophysiology. Considering the cell effects of the acute PDIA1 overexpression in vascular cells, the focus of this work is to investigate the role of PDIA1 on the processes of angiogenesis. In this investigation, we will approach such phenomena, specifically correlating them with PDIA1 overexpression. The specific aims are: 1) To validate a model of femoral artery occlusion and neovascularization in mice; 2) To investigate the effect of PDI overexpression on the neovascularization intensity; 3) To evaluate the functional implications of PDI overexpression on ischemic situations (i.e., assessing exercise time on treadmill). This investigation may provide novel evidence for redox mechanisms of angiogenesis mediated by PDIA1 in a relevant model. (AU)

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