Among the prostanoids, PGE2 is unique in that its actions are mediated by a family of four different E- prostanoid (EP) receptor isoforms. These receptors (EP1-4) have distinct tissue distributions and couple to disparate signaling pathways, providing a molecular basis for the range of functions attributed to PGE2 in the kidney and in other tissues. Thus, the impact of PGE2 generation on blood pressure may differ depending on its sites of synthesis and the resulting pattern of EP receptor activation. For example, we showed that the EP4 receptor is primarily responsible for triggering expression of renin at the juxtaglomerular apparatus (JGA) via the macula densa pathway. Furthermore, our preliminary studies using two novel mouse models show that: (1) cell-specific deletion of EP4 receptors in endothelium attenuates vasoconstrictor responses to angiotensin II and (2) generalized elimination of EP4 receptors confers substantial resistance to angiotensin II-dependent hypertension. Taken together, these findings suggest a consistent function for the EP4 receptor to promote increased blood pressure through independent mechanisms that include activating the RAS, promoting hypertensive effects of angiotensin II, and enhancing peripheral vascular resistance. The objective of the studies proposed here is to precisely define mechanisms linked to the EP4 receptor that may contribute to the pathogenesis of hypertension. Specifically, we will use genetically modified mouse models and EP4 receptor antagonists to provide new insights into the role of EP4 receptors in cardiovascular regulation. To this end, we will pursue the following Specific Aims: (1) To determine the specific role of EP4 receptors in the kidney in the pathogenesis of hypertension. (2) To establish the impact of EP4 receptor pools in the endothelium and vascular smooth muscle cells (VSMCs) on blood pressure control. (3) To define the contribution of EP4 receptors in the collecting duct to the regulation of blood pressure and renal excretory function. (4) To test the potential of the EP4 receptor as a therapeutic target in hypertension. The long-term goal of these experiments is to determine the potential of the EP4 receptor as a novel therapeutic target in hypertension.
High blood pressure is a major public health problem in the United States affecting more than 50 million individuals. Our proposal explores a novel pathway promoting the development of hypertension: activation of the EP4 receptor for prostaglandin E2. We will explore the mechanism used by the EP4 receptor to raise blood pressure and will define its potential utility as a therapeutic target for the treatment of hypertension.
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