Hypoxia inducible factor 1α in vascular smooth muscle cells promotes angiotensin II-induced vascular remodeling via activation of CCL7-mediated macrophage recruitment
Hypoxia inducible factor 1α in vascular smooth muscle cells promotes angiotensin II-induced vascular remodeling via activation of CCL7-mediated macrophage recruitment
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血管平滑肌细胞中的缺氧诱导因子1α通过激活CCL7介导的巨噬细胞募集促进血管紧张素II诱导的血管重塑
DOI：
10.1038/s41419-019-1757-0
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发表时间：
2019-07-18
影响因子：
9
通讯作者：
Qu, Aijuan
中科院分区：
文献类型：
--
作者：
Qi, Dan;Wei, Ming;Qu, Aijuan
血管重塑的过程与缺氧增加有关。然而，缺氧诱导因子1 α（HIF 1 α），介导细胞缺氧反应的关键转录因子，对血管重塑的贡献是确定的，但尚未完全理解。在血管紧张素II（Ang II）诱导的血管重塑模型中，HIF 1 α在血管平滑肌细胞（VSMCs）中增加并活化。选择性基因干扰HIF 1 α的VSMCs显着改善血管紧张素II诱导的血管重塑，显示降低血压，主动脉厚度，胶原沉积，炎症和主动脉僵硬。VSMC Hif 1 α缺陷也特异性抑制Ang II诱导的CD 45（+）CD 11b（+）F4/80（+）CD 206（-）M1巨噬细胞向血管的浸润。从机制上讲，VSMC中HIF 1 α的缺乏显著抑制了CCL 7的表达，CCL 7是巨噬细胞募集的关键趋化因子。生物信息学分析和染色质免疫沉淀分析揭示了Ccl 7启动子中的三个功能性缺氧反应元件，表明Ccl 7是HIF 1 α的直接靶基因。在体内用抗体阻断CCL 7减轻了Ang II诱导的高血压和血管重塑，与减少的巨噬细胞浸润一致。这项研究提供了直接的证据表明，HIF 1 α在VSMCs中的激活加剧了Ang II诱导的巨噬细胞浸润，并通过其靶基因Ccl 7导致血管重塑，因此可能作为重塑相关血管疾病的潜在治疗靶点。
The process of vascular remodeling is associated with increased hypoxia. However, the contribution of hypoxia-inducible factor 1 alpha (HIF1 alpha), 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, HIF1 alpha was increased and activated in vascular smooth muscle cells (VSMCs). Selective genetic disruption of Hif1 alpha in VSMCs markedly ameliorated Ang II-induced vascular remodeling, as revealed by decreased blood pressure, aortic thickness, collagen deposition, inflammation, and aortic stiffness. VSMC Hif1 alpha deficiency also specifically suppressed Ang II-induced infiltration of CD45(+)CD11b(+)F4/80(+)CD206(-) M1 macrophages into the vessel. Mechanistically, HIF1 alpha 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 HIF1 alpha 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 HIF1 alpha 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.