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Heparan sulfate proteoglycans as regulators of vascular tone

Grant number: 19/06653-2
Support type:Scholarships abroad - Research Internship - Post-doctor
Effective date (Start): October 01, 2019
Effective date (End): March 20, 2020
Field of knowledge:Biological Sciences - Pharmacology - Cardiorenal Pharmacology
Principal Investigator:Rita de Cassia Aleixo Tostes Passaglia
Grantee:Simone Regina Potje
Supervisor abroad: Andreia Zago Chignalia
Home Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
Local de pesquisa : University of Arizona, United States  
Associated to the scholarship:16/21239-0 - Structure of caveolae and its modulation on glycocalyx and the mechanotransducer process in essential hypertension, BP.PD

Abstract

The glycocalyx is a known regulator of eNOS activity and thus, a regulator o NO production. We have made the novel discovery that knockout animals for glypican-1 and syndecan-1, components of the glycocalyx, have impaired endothelium-dependent vasodilation and vasocontriction. These effects are more significant in the glypican-1 knockout (Gpc-1-/-) when compared to the syndecan-1 knockout (Sdc-1-/-) and thus we hypothesize that glypican-1 (Gpc-1) is the main proteoglycan acting as a vascular tone modulator. Furthermore, the absence of Gpc-1 and Scd-1 alters calcium dynamics in vascular cells by unknown mechanisms. Herein, we seek to evaluate the relative contribution of Gpc-1 and Sdc-1 to the regulation of vascular tone and to dissect the mechanisms that result in changes of calcium dynamics in vascular cells with resulting impaired vasoconstriction. We will explore how impaired vasoconstriction may relate to the control of blood pressure in these knockout mice. Syndecan-1 knockout (Sdc-1-/-), glypican-1 knockout (Gpc-1-/-) and wild-type mice (CD1 will be used as control to Gpc-1-/- and C57BL6 will be used as control to Sdc-1-/-) will be used in this study. We will promote silencing of Gpc-1 in aortic rings of Sdc-1-/-, silence Sdc-1 in aortic rings of Gpc-1-/- and rescue the expression of Gpc-1 and Sdc-1 in aortic rings of the global knockouts. We will perform experiments of vascular reactivity and assess myogenic response. Furthermore, calcium fluorescence will be assessed in isolated cells and aortic rings by confocal and spinning disc microscopy.