Grant: CIHR Fellowship

The primary objective of the proposal is to understand how hormones that circulate in the blood to regulate blood pressure alter the activity of the receptors that are expressed in blood vessels. We are interested in horomone called angiotensin II that activates angiotensin receptors. Angiotensin receptors are on the surface of cells that form blood vessels and the activation of these receptors leads to blood vessel constriction, hence, they are important for maintenance of normal blood pressure and heart function. Alterations in the receptor activity of angiotensin II has been shown to be associated with hypertension and congestive heart failure. Our goal is to better understand how other proteins expressed in blood vessels regulate the activity of these receptors under normal conditions and how changes in regulation of receptor activity lead to disease. We will investigate the effects of a loss in the expression of an enzyme called G protein-coupled receptor kinase 2 (GRK2), known to phosphorylate and inactivates the receptor. The loss of GRK2 results in altered angiotensin receptor signaling in blood vessels and leads to the development of hypertension in mice, but the exact mechanism remain largely unknown. We will utilize these hypertensive mice to understand the role of GRK2 in angiotensin II receptor signaling. We will also study a protein called Rab4 that controls the movement of receptors between different compartments in the cell. Therefore, we will assess the effect of changing Rab4 expression on angiotensin receptor delivery to the cell membrane via testing whether the overexpression of a malfunctioning Rab4 protein will generate hypertensive mice. Understanding the mechanism(s) by which angiotensin signaling is regulated is crucial to delineate the underlying pathways for the development and/or progression of hypertension. A better understanding of these pathways is key for the generation of novel approaches for treating cardiovascular disease.