Endothelial PPAR-γ Protects against vascular thrombosis by downregulating P-selectin expression

Abstract

Objective - We tested the hypothesis that endothelial peroxisome proliferator-activated receptor-γ protects against vascular thrombosis using a transgenic mouse model expressing a peroxisome proliferator-activated receptor-γ mutant (E-V290M) selectively in endothelium. Approach and Results - The time to occlusive thrombosis of the carotid artery was significantly shortened in E-V290M mice compared with nontransgenic littermates after either chemical injury with ferric chloride (5.1±0.2 versus 10.1±3.3 minutes; P=0.01) or photochemical injury with rose bengal (48±9 versus 74±9 minutes; P=0.04). Gene set enrichment analysis demonstrated the upregulation of NF-κB target genes, including P-selectin, in aortic endothelial cells from E-V290M mice (P<0.001). Plasma P-selectin and carotid artery P-selectin mRNA were elevated in E-V290M mice (P<0.05). P-selectin-dependent leukocyte rolling on mesenteric venules was increased in E-V290M mice compared with nontransgenic mice (53±8 versus 25±7 per minute; P=0.02). The shortened time to arterial occlusion in E-V290M mice was reversed by administration of P-selectin-blocking antibodies or neutrophil-depleting antibodies (P=0.04 and P=0.02, respectively) before photochemical injury. Conclusions - Endothelial peroxisome proliferator-activated receptor-γ protects against thrombosis through a mechanism that involves downregulation of P-selectin expression and diminished P-selectin-mediated leukocyte-endothelial interactions.