Abstract 93: Endothelial A Disintegrin and Metalloprotease 10 Deficiency Enhances Murine Atherosclerosis Development

Abstract

Through shedding of various membrane molecules, including adhesion molecules and chemokines, A Disintegrin And Metalloproteinase 10 (ADAM10) could regulate endothelial permeability and leukocyte recruitment, critical processes in inflammatory diseases like atherosclerosis. Indeed, proteomic analysis on mouse endothelial cell sheddome revealed ±300 differentially regulated proteins upon ADAM10 inhibition, of which 10% appeared involved in permeability and leukocyte transmigration. Accordingly, in vitro inhibition of endothelial ADAM10 decreased neutrophil adhesion and transmigration under flow. To evaluate the causal role of endothelial ADAM10 in atherosclerosis development, we used wildtype or endothelial ADAM10-deficient (ADAM10 fl/fl /Tie2-Cre; in brief ADAM10 del ) mice. Mice were rendered atherogenic by adeno-associated virus-mediated overexpression of PCSK9, resulting in persistent LDL receptor knockdown and hyperlipidemia after high cholesterol diet feeding (HCD). Surprisingly, after 12 weeks of HCD diet feeding, ADAM10 del mice showed significantly larger (±45%) and more advanced atherosclerotic lesions, with intraplaque hemorrhage in the brachiocephalic artery. Necrotic core area was increased (±87%) and macrophage content decreased (±49%). No differences were observed in granulocyte and collagen content. In contrast to the in vitro findings, in vivo endothelial permeability, leukocyte adhesion and extravasation, as assessed by intravital multiphoton microscopy, were all increased. In conclusion, this study reveals an unexpected protective effect of endothelial ADAM10 in atherosclerosis development. The underlying mechanisms remain to be determined.