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Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice.

ABSTRACT: OBJECTIVE:Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) has recently been shown to form an essential element of a mechanosensory complex that mediates endothelial responses to fluid shear stress. The aim of this study was to determine the in vivo role of PECAM-1 in atherosclerosis. METHODS AND RESULTS:We crossed C57BL/6 Pecam1(-/-) mice with apolipoprotein E-deficient (Apoe(-/-)) mice. On a Western diet, Pecam1(-/-)Apoe(-/-) mice showed reduced atherosclerotic lesion size compared to Apoe(-/-) mice. Striking differences were observed in the lesser curvature of the aortic arch, an area of disturbed flow, but not in the descending thoracic or abdominal aorta. Vascular cell adhesion molecule-1 (VCAM-1) expression, macrophage infiltration, and endothelial nuclear NF-kappaB were all reduced in Pecam1(-/-)Apoe(-/-) mice. Bone marrow transplantation suggested that endothelial PECAM-1 is the main determinant of atherosclerosis in the aortic arch, but that hematopoietic PECAM-1 promotes lesions in the abdominal aorta. In vitro data show that siRNA-based knockdown of PECAM-1 attenuates endothelial NF-kappaB activity and VCAM-1 expression under conditions of atheroprone flow. CONCLUSIONS:These results indicate that endothelial PECAM-1 contributes to atherosclerotic lesion formation in regions of disturbed flow by regulating NF-kappaB-mediated gene expression.

SUBMITTER: Harry BL

PROVIDER: S-EPMC2651147 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice.

Harry Brian L BL Sanders John M JM Feaver Ryan E RE Lansey Melissa M Deem Tracy L TL Zarbock Alexander A Bruce Anthony C AC Pryor Andrew W AW Gelfand Bradley D BD Blackman Brett R BR Schwartz Martin A MA Ley Klaus K

Arteriosclerosis, thrombosis, and vascular biology 20080807 11

<h4>Objective</h4>Platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) has recently been shown to form an essential element of a mechanosensory complex that mediates endothelial responses to fluid shear stress. The aim of this study was to determine the in vivo role of PECAM-1 in atherosclerosis.<h4>Methods and results</h4>We crossed C57BL/6 Pecam1(-/-) mice with apolipoprotein E-deficient (Apoe(-/-)) mice. On a Western diet, Pecam1(-/-)Apoe(-/-) mice showed reduced atherosclerotic lesi ...[more]

PMID: 18688018

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Project description:BackgroundNumerous genome-wide association studies revealed that SNPs (single nucleotide polymorphisms) at the PHACTR1 (phosphatase and actin regulator 1) locus strongly correlate with coronary artery disease. However, the biological function of PHACTR1 remains poorly understood. Here, we identified the proatherosclerotic effect of endothelial PHACTR1, contrary to macrophage PHACTR1.MethodsWe generated global (Phactr1-/-) and endothelial cell (EC)-specific (Phactr1ECKO) Phactr1 KO (knockout) mice and crossed these mice with apolipoprotein E-deficient (Apoe-/-) mice. Atherosclerosis was induced by feeding the high-fat/high-cholesterol diet for 12 weeks or partially ligating carotid arteries combined with a 2-week high-fat/high-cholesterol diet. PHACTR1 localization was identified by immunostaining of overexpressed PHACTR1 in human umbilical vein ECs exposed to different types of flow. The molecular function of endothelial PHACTR1 was explored by RNA sequencing using EC-enriched mRNA from global or EC-specific Phactr1 KO mice. Endothelial activation was evaluated in human umbilical vein ECs transfected with siRNA targeting PHACTR1 and in Phactr1ECKO mice after partial carotid ligation.ResultsGlobal or EC-specific Phactr1 deficiency significantly inhibited atherosclerosis in regions of disturbed flow. PHACTR1 was enriched in ECs and located in the nucleus of disturbed flow areas but shuttled to cytoplasm under laminar flow in vitro. RNA sequencing showed that endothelial Phactr1 depletion affected vascular function, and PPARγ (peroxisome proliferator-activated receptor gamma) was the top transcription factor regulating differentially expressed genes. PHACTR1 functioned as a PPARγ transcriptional corepressor by binding to PPARγ through the corepressor motifs. PPARγ activation protects against atherosclerosis by inhibiting endothelial activation. Consistently, PHACTR1 deficiency remarkably reduced endothelial activation induced by disturbed flow in vivo and in vitro. PPARγ antagonist GW9662 abolished the protective effects of Phactr1 KO on EC activation and atherosclerosis in vivo.ConclusionsOur results identified endothelial PHACTR1 as a novel PPARγ corepressor to promote atherosclerosis in disturbed flow regions. Endothelial PHACTR1 is a potential therapeutic target for atherosclerosis treatment.

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Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice.

Publications

Endothelial cell PECAM-1 promotes atherosclerotic lesions in areas of disturbed flow in ApoE-deficient mice.

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