Multi-scale Investigation of Sex Differences in Right Ventricular Function via Estrogen-Microtubule Interactions

Project Summary Pulmonary arterial hypertension (PAH) is a lethal disease with a median survival of only 5-7 years. Pathophysiologically, PAH is a progressive vasculopathy of the precapillary pulmonary vessels that increases pulmonary arterial pressures and pulmonary vascular resistance while reducing pulmonary arterial compliance. The changes in the pulmonary vasculature augment the work load of the right ventricle, which ultimately results in right ventricular dysfunction (RVD). The presence of RVD is the greatest risk factor for death in PAH; however, no current PAH therapies actually target the RV directly. In this proposal, we will investigate the hypothesis that sex-differences in RV function in PAH are in-part mediated by an inhibitory action of estrogen on microtubule dynamics. We will employ state of the art microscopy and computational analysis to define how estrogen regulates microtubules. Then, in translational studies we will determine modulation of the estrogen- microtubule interaction impacts right ventricular function in pre-clinical PAH using advanced hemodynamics and molecular phenotyping of the RV microtubule cytoskeleton.