Poliovirus Receptor-Related 2 A Cholesterol-Responsive Gene Affecting Atherosclerosis Development by Modulating Leukocyte Migration

Objective-Recently, poliovirus receptor-related 2 (Pvrl2) emerged as a top gene in a global gene expression study aiming to detect plasma cholesterol-responsive genes causally related to atherosclerosis regression in hypercholesterolemic mice. PVRL2 is an adherens junction protein implied to play a role in transendothelial migration of leukocytes, a key feature in atherosclerosis development. In this study, we investigated the effect of Pvrl2 deficiency on atherosclerosis development and transendothelial migration of leukocytes activity. Approach and Results-Pvrl2-deficient mice bred onto an atherosclerosis-prone background (Pvrl2(-/-)Ldlr(-/-)Apob(100/100)) had less atherosclerotic lesions and more stable plaques compared with littermate controls (Pvrl2(+/+)Ldlr(-/-)Apob(100/100)). Pvrl2(-/-)Ldlr(-/-)Apob(100/100) mice also showed a 49% decrease in transendothelial migration of leukocytes activity observed using the in vivo air pouch model. In accordance, augmented arterial wall expression of Pvrl2 during atherosclerosis progression coincided with an increased gene expression of migrating leukocytes into the vessel wall. Both in human and mice, gene and protein expression of PVRL2 was predominantly observed in the vascular endothelium according to the immunohistochemical and gene expression data. In addition, the cholesterol responsiveness of PVRL2 was also observed in humans. Conclusions-PVRL2 is a plasma cholesterol-responsive gene acting at endothelial sites of vascular inflammation that could potentially be a new therapeutic target for atherosclerosis prevention through its suggested transendothelial migration of leukocytes modulating activity.