Theranostics 2022; 12(4):1855-1869. doi:10.7150/thno.69017 This issue Cite

Research Paper

Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α

Yalan Wu1,2, Xiaolong Tang3,4, Sharen Lee1, Huiling Hong1,2, Xiaoyun Cao1,2, Chi Wai Lau1, Baohua Liu3,4, Ajay Chawla5, Ronald Ching Wan Ma6, Yu Huang1,2, Kathy O Lui2,7, Xiao Yu Tian1,2✉

1. School of Biomedical Sciences, Faculty of Medicine; Chinese University of Hong Kong, Hong Kong SAR, China.
2. CUHK Shenzhen Research Institute, Shenzhen, China.
3. Shenzhen Key Laboratory for Systemic Aging and Intervention (SAI), National Engineering Research Center for Biotechnology (Shenzhen), International Cancer Center, Shenzhen University, Shenzhen, China.
4. Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Shenzhen University, Shenzhen, China.
5. Department of Physiology, Department of Medicine, University of California San Francisco, CA 94143, United States.
6. Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, SAR, China.
7. Department of Chemical Pathology, Li Ka Shing Institute of Health Sciences, Chinese University of Hong Kong, Hong Kong SAR, China.

Citation:
Wu Y, Tang X, Lee S, Hong H, Cao X, Lau CW, Liu B, Chawla A, Ma RCW, Huang Y, Lui KO, Tian XY. Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α. Theranostics 2022; 12(4):1855-1869. doi:10.7150/thno.69017. https://www.thno.org/v12p1855.htm
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Abstract

Graphic 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 PPARδ activation enhances angiogenesis. However, how PPARδ 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 PPARδ in endothelial cells, whereas PPARδ reciprocally stabilized HIF1α protein to prevent its ubiquitin-mediated degradation. PPARδ directly bound to the oxygen-dependent degradation domain of HIF1α at the ligand-dependent domain of PPARδ. Importantly, this HIF1α-PPARδ interaction was independent of PPARδ ligand. Adeno-associated virus mediated endothelium-targeted overexpression of stable HIF1α 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 PPARδ in ECs stabilizes HIF1α and serves as a critical regulator for HIF1α activation to facilitate the post-ischemic restoration of vascular homeostasis.

Keywords: Endothelial cell, PPARδ, HIF1α, hindlimb ischemia, vascular homeostasis


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APA
Wu, Y., Tang, X., Lee, S., Hong, H., Cao, X., Lau, C.W., Liu, B., Chawla, A., Ma, R.C.W., Huang, Y., Lui, K.O., Tian, X.Y. (2022). Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α. Theranostics, 12(4), 1855-1869. https://doi.org/10.7150/thno.69017.

ACS
Wu, Y.; Tang, X.; Lee, S.; Hong, H.; Cao, X.; Lau, C.W.; Liu, B.; Chawla, A.; Ma, R.C.W.; Huang, Y.; Lui, K.O.; Tian, X.Y. Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α. Theranostics 2022, 12 (4), 1855-1869. DOI: 10.7150/thno.69017.

NLM
Wu Y, Tang X, Lee S, Hong H, Cao X, Lau CW, Liu B, Chawla A, Ma RCW, Huang Y, Lui KO, Tian XY. Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α. Theranostics 2022; 12(4):1855-1869. doi:10.7150/thno.69017. https://www.thno.org/v12p1855.htm

CSE
Wu Y, Tang X, Lee S, Hong H, Cao X, Lau CW, Liu B, Chawla A, Ma RCW, Huang Y, Lui KO, Tian XY. 2022. Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α. Theranostics. 12(4):1855-1869.

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