Study on the association between arterial collagen glycation and vascular dysfunction in mice exposed to advanced glycation endproducts

• Grant number: 24/00842-6
• Support Opportunities: Scholarships in Brazil - Master
• Start date: November 01, 2024
• End date: July 31, 2026
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Renato Simões Gaspar
• Grantee: Natália Silva Oliveira
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil

Abstract

Prolonged hyperglycemia leads to the formation of advanced glycation end products (AGEs) that generate tissue damage in diabetes. In this sense, endothelial dysfunction and vascular stiffening become key components in cardiovascular events in diabetic patients. Both effects may be linked to proteins with a long half-life of the extracellular matrix (ECM), such as type I collagen, which would be irreversibly modified by AGEs (glycation). However, it is not known whether collagen glycation is associated with a factor in vascular dysfunction caused by AGEs. In this way, we objectively evaluated whether collagen glycation in arteries of mice with high levels of circulating AGEs is associated with vascular dysfunction. Specifically, we will evaluate the AGE receptor (RAGE) pathway as a mechanism underlying the vascular dysfunction proposed here and test the effect of a commonly used medication, metformin. These objectives will be pursued through experiments with C57bl mice, which will be exposed to AGEs through the addition of methylglyoxal (MGO), a dicarbonyl compound of glucose metabolism, in drinking water (0.5% v/v) for 12 weeks, followed by 4 weeks without exposure to MGO. The wash-out period was designed to reduce the impact of the direct action of MGO or the glycation of short-half-life proteins in the assays. In the last two weeks the mice will be treated with metformin or azeliragon (RAGE inhibitor). These subjects make up the following experimental groups: healthy control, MGO, MGO + metformin, and MGO + azeliragon. At the end, the mice will be euthanized, and the aorta artery and blood will be collected. The aorta will be segmented into rings for vascular reactivity (relaxation and contraction), viscoelasticity, immunofluorescence and western blotting tests. The blood will be centrifuged to store plasma for ELISA tests (MGO measurement). MGO intervention is expected to induce endothelial dysfunction through reduced vascular relaxation and increased vessel deficiency, whereas azeliragon treatment improves vascular function. Therefore, we will use an isolated model of increased circulating AGEs to identify new mechanisms that are associated with vascular dysfunction as a new strategy to treat cardiovascular events in diabetic patients in the future.