Open AccessKnockdown of HIF ‐1α impairs post‐ischemic vascular reconstruction in the brain via deficient homing and sprouting bm EPC s
Author(s) -
Liu Yang,
Ran He,
Xiao Yaping,
Wang Hongjin,
Chen Yi,
Chen Weihai,
Xu Xiaoyu
Publication year - 2018
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/bpa.12628
Subject(s) - gene knockdown , homing (biology) , sprouting , small hairpin rna , neovascularization , progenitor cell , microbiology and biotechnology , angiogenesis , endothelial progenitor cell , chemistry , bone marrow , cancer research , biology , immunology , stem cell , apoptosis , ecology , biochemistry , botany
Although the critical role of hypoxia inducible factor‐1α ( HIF ‐1α) in cerebral neovascularization after stroke has been well characterized, the details regarding the regulation of endothelial progenitor cell ( EPC )‐dependent neovascularization by HIF ‐1α are not completely understood. Using lentiviral sh RNA to knockdown HIF ‐1α, we showed that HIF ‐1α plays a central role in bone marrow‐derived EPC (bm EPC ) homing and sprouting in the post‐acute stage of ischemic Sprague Dawley ( SD ) rat brains. First, knockdown of HIF ‐1α decreased the homing of both endogenous and exogenous bm EPC s to the ischemic brain. Additionally, the knockdown impaired the incorporation and sprouting of bm EPC s in the ischemic brain. In vitro , knockdown of HIF ‐1α inhibited the spheroid sprouting and tube formation of bm EPC s. Mechanically, the HIF ‐1α‐dependent recruitment of bm EPC s to the ischemic brain was relative to the CXCL 12/ CXCR 4 axis and HMGB 1, which were relative to astrocytes. In addition, the loss of HIF ‐1α resulted in deficient expression levels of VEGF ‐A, Flk‐1, NRP 1, and Dll4 in the ischemic brains, bm EPC s, and astrocytes. These findings suggested that HIF ‐1α implicates in bm EPC homing via CXCL 12/ CXCR 4 and HMGB 1 and that it promotes bm EPC sprouting via VEGF ‐A/flk1‐ NRP 1/Dll4.