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Overexpression of human EP4 receptor in vascular smooth muscle cells attenuates angiotensin II-induced hypertension in mice

XU Hu¹, WANG Sai-Lun¹, BAO Cheng-Zhen¹, YE Lan¹, GUAN You-Fei¹, ZHANG Xiao-Yan^2,*

¹Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China；²Health Science Center, East China Normal University, Shanghai 200241, China

Abstract

Prostaglandin E2 (PGE2) plays an important role in cardiovascular system. PGE2 regulates blood pressure through its 4 G protein coupled receptors, i.e., EP1, EP2, EP3, and EP4. The aim of this study was to investigate the role of EP4 receptors in vascular smooth muscle cells (VSMC) in blood pressure regulation. VSMC-specific human EP4 transgenic (VSMC-hEP4 Tg) mice were generated and genotyped. The systolic blood pressure (SBP) of the VSMC-hEP4 Tg mice and the wild-type (WT) littermates was measured under normal, low-salt (LSD) and high-salt diet (HSD) conditions using a tail-cuff method. Both WT and VSMC-hEP4 Tg mice were administered with a chronic infusion of angiotensin II (Ang II) with an osmotic pump and SBP levels were monitored every week. The mean arterial blood pressure (MAP) of WT and VSMC-hEP4 Tg mice upon Ang II intravenous infusion was measured via carotid arterial catheterization. Ang II-induced vasoconstriction of the mesenteric arterial rings from WT and VSMC-hEP4 Tg mice was measured using the multi myograph system. The effect of PGE1-OH (a selective EP4 agonist) on Ang II-induced phosphorylation of myosin phosphatase target subunit 1 (MYPT1) was detected by Western blot. The effect of two additional EP4 specific agonists (CAY10580 and CAY10598, 0.5 mg/kg) on blood pressure of WT mice was measured by carotid arterial catheterization. The results showed that the VSMC-hEP4 Tg mice were successfully generated and their basal SBP levels were lower than those of WT mice. Although blood pressure levels were significantly altered in WT mice under LSD and HSD, little change was observed in the VSMC-hEP4 Tg mice. After a chronic infusion and an acute intravenous injection of Ang II, SBP levels of VSMC-hEP4 Tg mice were significantly lower than those of WT mice. In addition, both CAY10580 and CAY10598 significantly reduced MAP levels of WT mice. Ex vivo study showed that treatment of isolated mesenteric arteries with PGE1-OH inhibited Ang II-induced phosphorylation of MYPT1. Collectively, these results demonstrate that specific overexpression of human EP4 gene in VSMCs significantly reduces basal blood pressure levels and attenuates Ang II-induced hypertension, possibly via inhibiting Ang II/AT1 signaling pathway. Our findings suggest that EP4 may represent an attractive target for the treatment of hypertension.

Key words: prostaglandin E2; EP4 receptor; Vascular smooth muscle cell; hypertension

Received: 2021-03-16　　Accepted: 2021-05-24

Corresponding author: 张晓燕　　E-mail: xyzhang@hsc.ecnu.edu.cn

DOI: 10.13294/j.aps.2021.0056

Citing This Article：

XU Hu, WANG Sai-Lun, BAO Cheng-Zhen, YE Lan, GUAN You-Fei, ZHANG Xiao-Yan. Overexpression of human EP4 receptor in vascular smooth muscle cells attenuates angiotensin II-induced hypertension in mice. Acta Physiol Sin 2021; 73 (4): 597-605 (in Chinese with English abstract).