Prostaglandins (PGs), oxidative metabolites of arachidonic acid, mediate an array of physiologic functions including inflammation and systemic blood pressure homeostasis. Prostaglandin E2 (PGE2) is a major regulator of blood pressure, where it exerts pro-hypertensive or anti-hypertensive effects depending upon the setting. These physiologically opposing effects are mediated by four PGE2 receptors, designated the E-Prostanoid (EP) receptors EP1 to EP4. Previous work by our group and others determined that EP1 and EP3 primarily mediate the pro-hypertensive response, while EP2 and EP4 receptors mediate the anti-hypertensive response. PGs are well characterized to be effectors of inflammation, and thus PGs act at the intersection of inflammation and blood pressure homeostasis, making them potential targets in the etiology of essential hypertension. Our hypothesis is that EP receptors regulate immune-inflammatory cells and a robust T-cell mediated immune response contributes to hypertension. Moreover, multiple, repeated stimulation of the T-cell response in the face of hypertensive stimuli such as salt loading is modulated by PGs to generate sustained elevated blood pressure. We hypothesize that the EP3 receptor is the principal receptor facilitating the PGE2 response to raise blood pressure. To test these related hypotheses we propose three Specific Aims: 1) Test the hypothesis that EP3 regulates the response to repeated pro-hypertensive stimuli leading to the development of memory T-cells underlying sustained elevation of blood pressure; 2) Test the hypothesis that elevated ROS leads to neoantigen stimulated T-cell formation; 3) Test the hypothesis that EP receptor expression on T-cells contributes to the generation of hypertension.
Studies delineating the role of E-prostanoid (EP) receptors in hypertension are the focus of the current proposal. Our hypothesis is that expression of EP receptors on cells of the immune-inflammatory compartment contributes to essential hypertension and that activation of the EP3 receptors expressed on T-cells and Dendritic Cells are key modulators of the adaptive immune response. The proposed studies are highly relevant to understanding mechanisms linking inflammation and hypertension as well as identifying novel targets for the treatment of hypertension.
