Abstract 464: Progesterone Signaling in Endothelial Cells Results in Increased Vascular Permeability and Platelet Adhesion

Abstract

Epidemiological studies have indicated the rather significant, yet unclear, impact of sex hormones on cardiovascular physiology and disease. Both observational studies and clinical trials have produced conflicting evidence as to the benefits of female sex hormones, particularly with regards to progesterone. Prolonged exposure to progesterone leads to break-through bleeding, vessel fragility and venous thromboembolisms. Currently, little is known on the molecular and cellular effects of progesterone on the cardiovascular system, or its cell specific functions. In fact, the vascular effects attributed to progesterone have been viewed, for the most part, as secondary consequences of its multiple systemic activities. Using a PRLacZ reporter mouse we have determined that progesterone receptor (PR) expression in the vasculature is restricted to endothelial cells of veins and lymphatics of the reproductive tract. Conditional deletion of PR from endothelial cells using VE-cadherin Cre leads to decreased vascular permeability in the uterus and ovary following treatment with progesterone. Transgenic misexpression of PR in the lung results in pathological vascular leakage and intravascular platelet adhesion in response to progesterone. Additionally, activation of PR within endothelial cells leads to the development of stress fibers, formation of inter-cellular gaps, increased permeability and changes in expression of cell-cell junctional proteins. These results reveal a previously unknown and direct role for PR on endothelial cell function with consequences for physiological permeability, blood vessel integrity and homeostasis.