Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α
Yalan Wu, Xiaolong Tang, Sharen Lee, Huiling Hong, Xiaoyun Cao, Chi Wai Lau, Baohua Liu, Ajay Chawla, Ronald C.W., Yü Huang, Kathy O. Lui, Xiao Yu Tian
Abstract
Rationale: Restoration of vascular perfusion in peripheral arterial disease involves a combination of neovessel formation and the functional restoration of vascular endothelium. Previous studies indicated that ligand-dependent PPAR activation enhances angiogenesis. However, how PPAR is triggered by hypoxia and its downstream effects during post-ischemic vascular repair was not well understood. Methods: We induced experimental hindlimb ischemia in endothelial cell selective Ppard knockout induced by Cdh5-Cre mediated deletion of floxed Ppard allele in mice and their wild type control and observed blood perfusion, capillary density, vascular relaxation, and vascular leakage. Results: Deletion of endothelial Ppard delayed perfusion recovery and tissue repair, accompanied by delayed post-ischemic angiogenesis, impaired restoration of vascular integrity, more vascular leakage and enhanced inflammatory responses. At the molecular level, hypoxia upregulated and activated PPAR in endothelial cells, whereas PPAR reciprocally stabilized HIF1 protein to prevent its ubiquitin-mediated degradation. PPAR directly bound to the oxygen-dependent degradation domain of HIF1 at the ligand-dependent domain of PPAR. Importantly, this HIF1-PPAR interaction was independent of PPAR ligand. Adeno-associated virus mediated endothelium-targeted overexpression of stable HIF1 in vivo improved perfusion recovery, suppressed vascular inflammation, and enhanced vascular repair, to counteract with the effect of Ppard knockout after hindlimb ischemia in mice. Conclusions: In summary, hypoxia-induced, ligand-independent activation of PPAR in ECs stabilizes HIF1 and serves as a critical regulator for HIF1 activation to facilitate the post-ischemic restoration of vascular homeostasis.