Abstract 210: Milk Fat Globule Epidermal Growth Factor VIII Mediates Vascular Remodeling by Increasing Inflammation and Smooth Muscle Activation

Abstract

Vascular remodeling, defined as a change in the geometry of the vessel wall, occurs in the pathological process of vascular diseases, like atherosclerosis, hypertension and restenosis. The resulting neointimal formation is a part of a reparative response including thrombosis, inflammatory cell infiltration, vascular smooth muscle cell (VSMC) proliferation and migration, which lead to the stenosis of blood vessels and the restricted blood flow. Milk fat globule epidermal growth factor VIII (Mfge8), a secreted glycoprotein, is well-characterized for its capacity of assisting the clearance of apoptotic cells in vascular system. Recently, Mfge8 has been identified as a pivot relay between pro-inflammatory signals and activated VSMCs, contributing to intima-media thickening of the vessel wall by promoting VSMC proliferation and migration in aged arteries. We have noted intense Mfge8 expression in the endothelial cells and VSMCs of the carotid artery following ligation injury in mice, suggesting that Mfge8 may regulate the two characteristics of vascular remodeling, inflammatory cell infiltration and VSMC activation, in response to low blood flow. To elucidate the functions of Mfge8 in a flow-induced model of vascular remodeling, a complete carotid ligation was conducted in wild-type (WT) or Mfge8 knockout (KO) mice. Morphometric analysis demonstrated that genetic deletion of Mfge8 in mice reduces carotid intima and media thickening compared to WT mice. Deficiency of Mfge8 prevented VSMC phenotypic modulation, as evidenced by the decreased expression of smooth muscle myosin heavy chain and attenuated cell proliferation in tunica media after ligation injury. VSMCs transfected with SiRNA against Mfge8 migrated slower than in controls as early as 0.5 days post-platelet-derived growth factor (PDGF) stimulation. Further, Mfge8-null mice showed a dramatic decrease in leukocyte infiltration into the vessel wall. Collectively, in a flow-induced model of vascular remodeling, Mfge8 plays a crucial role in VSMC migration and proliferation, as well as inflammatory cell accumulation, thereby regulating neointimal formation.