title: Ang II induces capillary formation from endothelial cells via the AT1R-dependent inositol requiring enzyme 1 pathway.
abstract: Previous studies have demonstrated an important interaction between angiotension II type 1 receptor (AT1R) and angiotension II (Ang II) -induced capillary formation from endothelial cells and vascular endothelial growth factor (VEGF). However, the underlying mechanism remains elusive. Recent studies revealed that the unfolded protein response regulates an angiogenic response by the kidney epithelium during ischemic stress. Therefore, in the present study, we investigated the effects of Ang II on AT1R-mediated capillary formation from endothelial cells and the possible involvement of the IRE1/JNK/p38 MAPK pathway. Our results show that Ang II (1 nmol/L) induced the expression of VEGF and enhanced capillary formation from endothelial cells in the Matrigel assay. This effect was significantly depressed by the AT1R blocker losartan and different inhibitors (irestatin, IRE1 specific inhibitor; SP600125, JNK specific inhibitor; SB203580, p38 MAPK specific inhibitor) but not by the AT2R blocker PD123319. Next, we investigated the effect of Ang II on the IRE1/JNK/p38 MAPK pathway and the 78kDA glucose regulated protein 78 (GRP78) activity in HUVECs and the role of the AT1 Receptor. The results show that Ang II activated both the IRE1/JNK/p38 MAPK pathway and GRP78 binding activity. These effects were markedly inhibited by the AT1R blocker losartan. The IRE1 specific inhibitor irestatin, the JNK specific inhibitor SP600125, and the p38 MAPK specific inhibitor SB203580 significantly inhibited Ang II-induced capillary formation from endothelial cells and VEGF expression but had no effect on GRP78. Collectively, these findings suggest for the first time that Ang II promotes capillary formation by inducing the expression of VEGF via Ang II type 1 receptor-mediated stimulation of the IRE1/JNK/p38 MAPK pathway.
authors.affiliation: Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha 410078, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Wang
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Bai
authors.forename: Dan
authors.initials: D
authors.lastname: Hong
authors.forename: Hai-Chao
authors.initials: HC
authors.lastname: Gao
authors.forename: Ling-Fang
authors.initials: LF
authors.lastname: Li
authors.forename: Chuan-Chang
authors.initials: CC
authors.lastname: Li
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Zhu
authors.forename: Quan
authors.initials: Q
authors.lastname: Sun
authors.forename: Guo-Gang
authors.initials: GG
authors.lastname: Zhang
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D001483:Base Sequence; D002196:Capillaries / Q000187:drug effects*; D002478:Cells, Cultured; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases