The role of GRIP1 and ephrin B3 in blood pressure control and vascular smooth muscle cell contractility.

Yujia Wang,W Edward Bradley,Shenjiang Hu,Georg B Ehret,Zhao Qin,Zenghui Wu,John Raelson,Guy Cloutier,Ekatherina Stoyanova,Patricia B Munroe,Junzheng Peng,Jian-Zhong Shen,Hongyu Luo,Jiangping Wu,Tao Wu

doi:10.1038/srep38976

Abstract

Several erythropoietin-producing hepatocellular receptor B family (EPHB) and their ligands, ephrinBs (EFNBs), are involved in blood pressure regulation in animal models. We selected 528 single nucleotide polymorphisms (SNPs) within the genes of EPHB6, EFNB2, EFNB3 and GRIP1 in the EPH/EFN signalling system to query the International Blood Pressure Consortium dataset. A SNP within the glutamate receptor interacting protein 1 (GRIP1) gene presented a p-value of 0.000389, approaching the critical p-value of 0.000302, for association with diastolic blood pressure of 60,396 individuals. According to echocardiography, we found that Efnb3 gene knockout mice showed enhanced constriction in the carotid arteries. In vitro studies revealed that in mouse vascular smooth muscle cells, siRNA knockdown of GRIP1, which is in the EFNB3 reverse signalling pathway, resulted in increased contractility of these cells. These data suggest that molecules in the EPHB/EFNB signalling pathways, specifically EFNB3 and GRIP1, are involved blood pressure regulation.

Highlights

Several erythropoietin-producing hepatocellular receptor B family (EPHB) and their ligands, ephrinBs (EFNBs), are involved in blood pressure regulation in animal models
Our previous studies[22,23] along with some of our unpublished observations indicate that molecules in the EPHB and EFNB families (e.g., EPHB6, EFNB1, EFNB2, and EFNB3) and a certain adaptor protein (GRIP1) within their signalling pathways are novel factors that can modulate blood pressure (BP) in mice
We queried the results of this meta-analysis for association of 528 single nucleotide polymorphisms (SNPs) in EPHB6, EFNB2, EFNB3 and glutamate receptor interacting protein 1 (GRIP1) genes with systolic or diastolic pressure in these individuals

Summary

Introduction

Several erythropoietin-producing hepatocellular receptor B family (EPHB) and their ligands, ephrinBs (EFNBs), are involved in blood pressure regulation in animal models. In vitro studies revealed that in mouse vascular smooth muscle cells, siRNA knockdown of GRIP1, which is in the EFNB3 reverse signalling pathway, resulted in increased contractility of these cells. These data suggest that molecules in the EPHB/EFNB signalling pathways, EFNB3 and GRIP1, are involved blood pressure regulation. Erythropoietin-producing hepatocellular receptor (EPH) kinases are the largest family of receptor tyrosine kinases They are divided into A and B subfamilies according to sequence homology[1]. In the absence of such reverse signaling, such as the case of EPHB6 KO, the VSMC contractility will increase, resulting higher BP

Methods

Results

Conclusion