Endothelial PPARδ is involved in Functional Recovery in Mouse Model of Hindlimb Ischemia
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AbstractIntroduction: Peripheral arterial disease (PAD) is a vascular disease occurs in the lower limb caused by ischemia due to atherosclerotic occlusion. It is a common vascular complication in patients with diabetes. Previous studies indicated potential function of PPARδ to enhance angiogenesis and inhibit inflammation, while the detailed mechanism is not fully understood.

Hypothesis: We aim to study whether endothelial PPARδ is important for vascular repair in mouse model of hindlimb ischemia and the possible mechanisms involved.

Methods: Endothelial cell (EC) specific knockout of Ppard was achieved by assembling PpardfloxP/floxP mice with Cdh5Cre/+ mice to generate Pparδf/f (or PparδEC-WT) as wild type, and Pparδf/f;Cdh5Cre/+ (or PparδEC-KO) as endothelium-specific Ppard knockout mice. Hindlimb ischemia was performed by ligation of the femoral artery, and blood flow recovery was monitored by Laser Doppler imaging. Low limb muscles from the injured and uninjured legs were used for flow cytometric, mRNA/protein expression, histology.

Results and conclusions: Ppard deficiency in ECs attenuated the restoration of blood flow recovery over a two-week period in lean mice, which was further inhibited in obese mice fed with high fat diet. This effect is accompanied by reduced muscle mass, more severe inflammatory cell infiltration, fibrotic scar replacement of muscle fibers, and less neovascularization. Unresolved vascular inflammation in the ischemia muscle of PpardEC-KO mice was accompanied by higher expressions of pro-inflammatory chemokines and adhesion molecules, and infiltration of macrophages and T lymphocytes. The appearance of CD133+CD34+CXCR4+ endothelial progenitor cells (EPC) and KDR expression on Lin-Sca1+c-kit+ hematopoietic stem cells was reduced in the ischemic muscle of PpardEC-KO mice. Such changes were accompanied with decreased expression of CXCL12 and CXCR4 in ischemic tissue with Ppard deficiency. In mouse endothelial cell line, angiogenesis and migration can be enhanced by PPARδ agonist and inhibited by Ppard siRNA. Our result indicate PPARδ is involved in vascular regeneration through multiple effects including angiogenesis, EPC mobilization, as well as inhibition of vascular inflammation.
All Author(s) ListYalan WU, Sharen LEE, Yu Huang, Kathy Oi Lan LUI, Xiao Yu TIAN
Name of ConferenceVascular Discovery: From Genes to Medicine 2019 Scientific Sessions
Start Date of Conference14/05/2019
End Date of Conference16/05/2019
Place of ConferenceBoston, Massachusetts, USA
Country/Region of ConferenceUnited States of America
Proceedings TitleArteriosclerosis, Thrombosis, and Vascular Biology
Year2019
Month5
Volume Number39
Issue NumberSuppl 1
LanguagesEnglish-United States

Last updated on 2019-22-10 at 09:45