نبذة مختصرة : Peripheral arterial disease (PAD) is a common vascular disease occurs in the lower limb caused by ischemia due to atherosclerotic occlusion. Accumulation of fatty deposits in the vessel wall narrows the artery and reduce blood flow to limbs, causing ischemia, tissue damage and may eventually leads to critical limb ischemia, tissue necrosis, and amputation. It is a common vascular complication in patients with hyperlipidemia and hyperglycemia. Restoration of vascular perfusion in PAD involves the functional recovery of the vascular endothelium. Emerging experimental and clinical evidence show that the peroxisome proliferator-activated receptor delta (PPARδ), participates in enhancing angiogenesis and inhibiting inflammation, based mostly on studies using ligand-dependent activation of PPARδ. However, how PPARδ may be triggered by hypoxic stress and its downstream effects during post-ischemic vascular repair and muscle regeneration were not well understood. ; In the first part of this thesis, we investigated the role of PPARδ in hindlimb ischemia mouse model. By constructing two in vivo mouse models: endothelial cell-specific knockout PPARδ mice and endothelial cells-specific overexpressing PPARδ in mice, I found that endothelial PPARδ effectively restored reperfusion of ischemic hindlimbs, improved regeneration of injured muscles, inhibited vascular inflammation, improved recovery endothelial function, and enhanced endothelial integrity. ; In the second part of this thesis, the results of single-cell transcriptome sequencing (scRNA-seq) revealed that selective deletion of PPARδ in endothelial cells caused significant changes in hypoxia-related signaling pathways and gene sets related to angiogenesis, endothelial permeability, and inflammatory response after ischemia. The results of in vivo mouse model and in vitro cell culture proved that deletion of PPARδ in endothelial cells hindered angiogenesis caused by hypoxia. ; In addition, after ischemia, loss of endothelial PPARδ caused a stronger inflammatory response, ...
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