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GPER inhibits diabetes-mediated RhoA activation to prevent vascular endothelial dysfunction.
Eur J Cell Biol. 2016 Feb;95(2):100-13. doi: 10.1016/j.ejcb.2015.12.002. Epub 2015 Dec 29.
Li Z1, Cheng L2, Liang H2, Duan W2, Hu J3, Zhi W2, Yang J2, Liu Z2, Zhao M4, Liu J5.
1Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China; Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Cardiovascular Surgery, General Hospital of Lanzhou Command, PLA, Lanzhou, China.
2Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
3Department of Pharmacy, General Hospital of Lanzhou Command, PLA, Lanzhou, China.
4Department of Pharmacology, School of Pharmacy, Fourth Military Medical University, Xi'an, China. Electronic address: minggao@fmmu.edu.cn.
5Department of Cardiovascular Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China. Electronic address: jingchengliu@163.com.
Abstract
The effect of estrogen receptors on diabetes-induced vascular dysfunction is critical, but ambiguous. Individuals with diabetic vascular disease may require estrogen receptor-specific targeted therapy in the future. The G protein-coupled estrogen receptor (GPER) has beneficial effects on vascular function. However, its fundamental mechanisms are unclear. The RhoA/Rho-kinase pathway contributes to diabetic vascular complications, whereas estrogen can suppress Rho-kinase function. Thus, we assumed that GPER inhibits diabetes-mediated RhoA activation to prevent vascular dysfunction. We further investigated the underlying mechanisms involved in this process. Vascular endothelial cells and ex vivo cultured ovariectomized (OVX) C57BL/6 mouse aortae were treated with high glucose (HG) alone or in combination with GPER agonist (G1). G1 treatment was also administered to OVX db/db mice for 8 weeks. An ex-vivo isovolumic myograph was used to analyze the endothelium-dependent vasodilation and endothelium-independent contraction of mouse aortae. Apoptosis, oxidative stress, and inflammation were attenuated in G1-pretreated vascular endothelial cells. G1 significantly decreased the phosphorylation of inhibitory endothelial nitric oxide (NO) synthase residue threonine 495 (eNOS Thr495), inhibited RhoA expression, and increased NO production. Additionally, G1 rescued the impaired endothelium-dependent relaxation and inhibited RhoA activation in the thoracic aorta of OVX db/db mice and ex-vivo cultured OVX C57BL/6 mouse aortae treated with HG. Estrogens acting via GPER could protect vascular endothelium, and GPER activation might elicit ERα-independent effect to inhibit RhoA/Rho-kinase pathway. Additionally, GPER activation might reduce vascular smooth muscle contraction by inhibiting RhoA activation. Thus, the results of the present study suggest a new therapeutic paradigm for end-stage vascular dysfunction by inhibiting RhoA/Rho-kinase pathway via GPER activation.
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