AUTHOR=Yang Xue-Feng , Wang Huan , Huang Yue , Huang Jian-Hua , Ren Hao-Lin , Xu Qian , Su Xiao-Min , Wang Ai-Mei , Ren Fu , Zhou Ming-Sheng 

TITLE=Myeloid Angiotensin II Type 1 Receptor Mediates Macrophage Polarization and Promotes Vascular Injury in DOCA/Salt Hypertensive Mice

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.879693

DOI=10.3389/fphar.2022.879693

ISSN=1663-9812

ABSTRACT=Activation of renin-angiotensin system has implicated in hypertension. Angiotensin (Ang) II is a potent proinflammatory mediator. The present study investigated the role of angiotensin type 1 receptor (AT1R) in control of macrophage phenotype in vitro and vascular injury in deoxycorticosterone acetate (DOCA)/salt hypertension. In human THP-1/macrophages and RAW264.7 macrophages, Ang II increased mRNA expressions of M1 cytokines and decreased M2 cytokine expressions. Overexpression of AT1R further increased Ang II-induced expressions of M1 cytokines and decreased M2 cytokines. Silenced AT1R reversed Ang II-induced changes in M1 and M2 cytokines. Ang II upregulated hypoxia inducible factor (HIF)1α, toll-like receptor (TLR)4 and the ratio of pIκB/IκB, which were prevented by silenced AT1R. Silenced HIF1α prevented Ang II activation of TLR4/NFκB pathway. Furthermore, Ang II increased HIF1α via reactive oxygen species-dependent reduction in prolyl hydroxylase domain protein 2 (PHD2) expression. The expressions of AT1R and HIF1α and the ratio of pIκB/IκB were upregulated in the peritoneal macrophages of DOCA hypertensive mice, specific deletion of myeloid AT1R attenuated cardiac and vascular injury and improved endothelial function accompanied by a reduction in aortic ROS production and M1 cytokine expressions and macrophage recruitment without significant reduction in blood pressure. Our results demonstrate that Ang II/AT1R controls macrophage phenotype via the stimulation of HIF1α/NFκB pathway, specific myeloid AT1R KO improves endothelial function, vascular inflammation and injury in salt-sensitive hypertension. The results support the notion that myeloid AT1R plays an important role in regulation of macrophage phenotype, and dysfunction of this receptor may promote hypertensive vascular dysfunction and injury.