1 Division of Nephrology Department of Medicine Duke University Durham NC.
3 Renal Section Durham VA Medical Center Durham NC.
J Am Heart Assoc. 2019 Feb 19;8(4):e010745. doi: 10.1161/JAHA.118.010745.
Background Prostaglandin E ( PGE ) is a major prostanoid with multiple actions that potentially affect blood pressure ( BP ). PGE acts through 4 distinct E-prostanoid ( EP ) receptor isoforms: EP 1 to EP 4. The EP 4 receptor ( EP 4R) promotes PGE -dependent vasodilation, but its role in the pathogenesis of hypertension is not clear. Methods and Results To address this issue, we studied mice after temporal- and cell-specific deletion of EP 4R. First, using a mouse line with loss of EP 4 expression induced universally after birth, we confirm that EP 4R mediates a major portion of the acute vasodilatory effects of infused PGE . In addition, EP 4 contributes to control of resting BP , which was increased by 5±1 mm Hg in animals with generalized deficiency of this receptor. We also show that EP 4 is critical for limiting elevations in BP caused by high salt feeding and long-term infusion of angiotensin II . To more precisely identify the mechanism for these actions, we generated mice in which EP 4R loss is induced after birth and is limited to smooth muscle. In these mice, acute PGE -dependent vasodilation was attenuated, indicating that this response is mediated by EP 4R in vascular smooth muscle cells. However, absence of EP 4R only in this vascular compartment had a paradoxical effect of lowering resting BP , whereas the protective effect of EP 4R on limiting angiotensin II-dependent hypertension was unaffected. Conclusions Taken together, our findings support a complex role for EP 4R in regulation of BP and in hypertension, which appears to involve actions of the EP 4R in tissues beyond vascular smooth muscle cells.
背景 前列腺素 E ( PGE ) 是一种具有多种作用的主要前列腺素，可能会影响血压 ( BP ) 。 PGE 通过 4 种不同的 E 型前列腺素 ( EP ) 受体亚型发挥作用：EP1 到 EP4 。 EP4 受体 ( EP4R ) 促进 PGE 依赖性血管舒张，但它在高血压发病机制中的作用尚不清楚。
方法和结果 为了解决这个问题，我们研究了时空和细胞特异性缺失 EP4R 的小鼠。首先，我们使用一种在出生后普遍诱导 EP 表达缺失的小鼠系，证实 EP4R 介导了输注 PGE 引起的大部分急性血管舒张作用。此外，EP4 有助于控制静息血压，在普遍缺乏这种受体的动物中，血压升高了 5±1mmHg。我们还表明，EP4 对于限制高盐饮食和长期输注血管紧张素 II 引起的血压升高至关重要。为了更精确地确定这些作用的机制，我们生成了出生后诱导并限制于平滑肌的 EP4R 缺失的小鼠。在这些小鼠中，急性 PGE 依赖性血管舒张作用减弱，表明该反应是由血管平滑肌细胞中的 EP4R 介导的。然而，仅在这个血管部位缺失 EP4R 会产生降低静息血压的反常作用，而 EP4R 对限制血管紧张素 II 依赖性高血压的保护作用不受影响。
结论 综上所述，我们的发现支持 EP4R 在调节血压和高血压中的复杂作用，这似乎涉及 EP4R 在血管平滑肌细胞以外的组织中的作用。
