Epi/pericellular protein disulfide isomerase: a novel regulator of biomechanical adaptation in vascular cells

• Grant number: 13/17115-5
• Support Opportunities: Scholarships in Brazil - Post-Doctorate
• Effective date (Start): April 01, 2014
• Effective date (End): August 31, 2018
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Francisco Rafael Martins Laurindo
• Grantee: Leonardo Yuji Tanaka
• Host 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
• Associated research grant: 13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID
• Associated scholarship(s): 15/15281-0 - Characterization and mechanisms of microRNA-mediated paracrine signaling involving protein disulfide isomerase-dependent mechano-adaptation in vascular cells, BE.EP.PD

Abstract

Adaptation to mechanical forces is a particularly relevant theme with respect to regulation of the vascular system. Previous data show that constrictive remodeling after injury is redox-mediated. Recently, we showed that protein disulfide isomerase (a redo chaperone from the endoplasmic reticulum) in its epi/pericellular localization (epcPDI) has an anti-constrictive remodeling effect during vascular repair after injury, via mechanisms that maintain vascular architecture with respect to collagen matrix and stress fiber organization. Such effects of epcPDI in the cytoskeleton are recapitulated in models of cyclic stretch, in which there is prevention of stress fiber disruption by a RhoA activator. In both models, epcPDI inhibition leads to RhoA clusterization. This project aims to elucidate the mechanobiology of this process in a new hierarchical level of investigation, examining in cells the hypothesis that epcPDI acts as a regulator of cytoskeletal architecture, via RhoA, in the course of morpho-functional adaptations to mechanical stimuli. Specific aims are: 1) To validate and dvelop mehthodological tools aiming to characterize mechanisms of adaptation to mechanical stimuli; 2) To investigate, using methods that include techniques for localized real-time analysis, the effects of epcPDI in mechanoadaptation, as well as possible functional and structural interactions among PDI, RhoA and RhoGDI in respondse to mechanical stresses; 3) To assess whether the possible convergence between epcPDI and RhoA involves redox pathways; 4) To investigate a functional model of redox-dependent convergence between epcPDI and RhoA in the modulation of vascular remodeling in vivo. Elucidation of these mechanisms can identify a role of epcPDI and redox processes at the cell surface in the regulation of cell tensegrity, bringing widespread implications.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

TANAKA, LEONARDO Y.; LAURINDO, FRANCISCO R. M.. Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation. Free Radical Biology and Medicine, v. 109, n. SI, p. 11-21, AUG 2017. (13/17115-5, 09/54764-6, 13/07937-8)

TANAKA, LEONARDO Y.; ARAUJO, THAIS L. S.; RODRIGUEZ, I, ANDRES; FERRAZ, MARIANA S.; PELEGATI, VITOR B.; MORAIS, MAURO C. C.; DOS SANTOS, ALINE M.; CESAR, CARLOS L.; RAMOS, ALEXANDRE F.; ALENCAR, ADRIANO M.; et al. Peri/epicellular protein disulfide isomerase-A1 acts as an upstream organizer of cytoskeletal mechanoadaptation in vascular smooth muscle cells. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, v. 316, n. 3, p. H566-H579, MAR 2019. (13/17115-5, 15/06210-2, 13/07937-8)

TANAKA, LEONARDO Y.; LAURINDO, FRANCISCO R. M.. Vascular remodeling: A redox-modulated mechanism of vessel caliber regulation. Free Radical Biology and Medicine, v. 109, n. SI, p. 11-21, AUG 2017. (13/17115-5, 13/07937-8, 09/54764-6)