Abstract 070: The Prostaglandin Ep4 Receptor in Endothelium Modulates eNos Expression and Aortic Integrity

Prostaglandin EP4 receptor (EP4R) plays pivotal role in mediating PGE2-induced vasodilation and blood pressure homeostasis. Our previous work demonstrated that absence of EP4R in all tissues was associated with salt sensitivity and exaggerated Ang II-dependent hypertension. While cell-specific elimination of EP4R from vascular smooth muscle cells (VSMCs) attenuated EP4-dependent vasodilation, but the severity of Ang II-dependent hypertension was not affected. These findings indicate the effects of EP4R to resist hypertension are not attributable to the compensatory vasodilation mediated by EP4R in VSMCs and must be mediated by other cell lineages. Within the vasculature, endothelial cells (ECs) also express high levels of EP4R. To assess the role of EP4R in ECs, we generated conditional EC-specific EP4R knockout mice mice using Tie2-CreERT2 and EP4 flox/flox mouse lines (ECKO). After pre-treatment with tamoxifen, we measured the blood pressure in conscious mice using radiotelemetry. At baseline, there were no significant differences in blood pressure between ECKO and controls 107.9±1.7 VS 109.3±1 mmHg). The response of ECKOs to Ang II infusion was variable. In one cohort, MAP during Ang II infusion was significantly lower than controls (142.8±3.1 vs 133.2±1.9 mmHg, p=0.02) whereas in a second cohort there was no difference in MAP with Ang II infusion between groups (131.7±2.3 vs 135.6±2.1 mmHg). Interestingly, the incidence of aortic aneurysm was significantly higher in ECKOs (12/27) compared to controls (2/25; p=0.01 by Fisher exact test). As urine sodium excretion during Ang II infusion was increased in ECKOs, we considered the possibility that aneurysm formation may have impacted the blood pressure. We also found the ECs isolated from ECKOs have significantly higher eNOS mRNA expression compared to control (fold change: 1.35±0.13; p=0.046). To determine whether this difference in eNOS expression have a functional impact, we compared blood pressure responses to L-NAME following Ang II infusion. ECKOs showed exaggerated response to L-NAME compared to controls (MAP increases +5.2±1.4 mmHg in ECKO vs. +0.5±1.5 mmHg in control; p=0.03). Thus, EP4R in ECs play important role in regulating EC function, impacting blood pressure and aortic integrity.