We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Hypoxia inducible factor 1α in vascular smooth muscle cells promotes angiotensin II-induced vascular remodeling via activation of CCL7-mediated macrophage recruitment.
- Authors
Qi, Dan; Wei, Ming; Jiao, Shiyu; Song, Yanting; Wang, Xia; Xie, Guomin; Taranto, Joseph; Liu, Ye; Duan, Yan; Yu, Baoqi; Li, Huihua; Shah, Yatrik M.; Xu, Qingbo; Du, Jie; Gonzalez, Frank J.; Qu, Aijuan
- Abstract
The process of vascular remodeling is associated with increased hypoxia. However, the contribution of hypoxia-inducible factor 1α (HIF1α), the key transcription factor mediating cellular hypoxic responses, to vascular remodeling is established, but not completely understood. In the angiotensin II (Ang II)-induced vascular remodeling model, HIF1α was increased and activated in vascular smooth muscle cells (VSMCs). Selective genetic disruption of Hif1a in VSMCs markedly ameliorated Ang II-induced vascular remodeling, as revealed by decreased blood pressure, aortic thickness, collagen deposition, inflammation, and aortic stiffness. VSMC Hif1a deficiency also specifically suppressed Ang II-induced infiltration of CD45+CD11b+F4/80+CD206− M1 macrophages into the vessel. Mechanistically, HIF1α deficiency in VSMCs dramatically suppressed the expression of CCL7, a chemokine critical for macrophage recruitment. Bioinformatic analysis and chromatin immunoprecipitation assays revealed three functional hypoxia-response elements in the Ccl7 promoter, indicating that Ccl7 is a direct HIF1α target gene. Blocking CCL7 with antibody in vivo alleviated Ang II-induced hypertension and vascular remodeling, coincident with decreased macrophage infiltration. This study provides direct evidence that HIF1α activation in VSMCs exacerbates Ang II-induced macrophage infiltration and resultant vascular remodeling via its target gene Ccl7, and thus may serve as a potential therapeutic target for remodeling-related vascular disease.
- Publication
Cell Death & Disease, 2019, Vol 10, Issue 8, pN.PAG
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-019-1757-0