Investigating the role of Rac1 in cardiovascular development

Abstract

Rac1 is a Rho GTPase which is involved in a variety of fundamental cellular processes, such as cell proliferation, adhesion and migration. In the adult heart, Rac1 is upregulated in cardiovascular disease and is required for the development of hypertrophy through production of oxidative stress. However, its expression and function during cardiovascular development remains unclear. Rac1 gene expression was characterised during mouse cardiac development, and using Cre-loxP technology it was identified that Rac1 is essential in the cardiomycoytes within the myocardium, but not in the epicardium, for the normal development of the mouse embryonic heart. Deletion of Rac1 specifically in the cells of the myocardium, the cardiomyocytes, using the TnT-Cre transgenic mouse line, resulted in severe defects of the ventricular myocardial wall as well as disrupted cardiac outflow tract alignment. Rac1TnTCre mutants displayed disrupted formation of ventricular trabeculae early in development. This resulted in abnormalities in the mature structures that form from the trabeculae, including the compact myocardial wall and interventricular septum. As a consequence of these myocardial defects, Rac1TnTCre mutant hearts become dilated and ballooned in shape leading to malalignment of the cardiac outflow tract, but with no overall loss of cardiomyocytes. This thesis shows that Rac1 and interacting partners, Mena and Vav2, are required for the organisation and movement of cardiomyocytes in the ventricular myocardial wall during early trabeculae formation. Congenital heart defects, including those affecting the myocardium and outflow tract, are the most common form of birth abnormalities. Additionally, defects occurring in utero can predispose to heart disease in later life. Therefore, understanding the role of genes that regulate myocardial wall and outflow tract formation could facilitate the development of preventative measures and treatments for congenital heart defects and cardiovascular disease.