The Roles of Milk Fat Globule Epidermal Growth Factor (MFG-E8) in Vascular Remodeling

Cardiovascular disease remains a leading cause of mortality in Taiwan and other countries. The percutaneous transluminal coronary angioplasty (PTCA) with stents is the most well-­‐established procedure; however, restenosis of the vessel usually occurs after this angioplasty, resulting in the lumen renarrowning and restricted blood flow. Therefore, completely understanding the molecular mechanisms underlying the pathological processes of vascular diseases in order to explore the effective therapies and treatment strategies is crucially important. Pathological vascular remodeling occurs in response to hemodynamic changes or vascular injuries derived from vascular diseases, like hypertension, atherosclerosis, angioplasty and restenosis. The processes of vascular remodeling are composed of complicated interplays among endothelium activation, vascular inflammation, vascular smooth muscle cell (VSMC) phenotypic modulation and extracellular matrix (ECM) degradation/deposition, leading to neointimal formation with narrowing lumen. Recently, milk fat globule epidermal growth factor VIII (Mfge8), a secretory protein with multiple functional domains, has been identified as a novel modulator in vascular remodeling. Mfge8 is known to initiate intracellular signaling cascades via ligating to integrin. Mfge8 also plays a role in degrading interstitial collagen I. Our preliminary data demonstrated that Mfge8 is highly expressed in endothelial cells, VSMCs and leukocytes of injured vessels. In addition, our Mfge8-­‐deficient mice develop less intima-­‐media thickening with decreased leukocyte infiltration and VSMC proliferation/migration in the injured vessels. Therefore, in this application, we will test the global hypothesis that Mfge8 increases neointimal formation by enhancing the endothelial permeability with increased leukocyte infiltration, promoting VSMC proliferation/migration, and facilitating collagen I degradation in the vessel wall. The specific aims to support our hypothesis are: 1) to determine whether Mfge8 and its molecular domains increase inflammation-­‐induced endothelial barrier dysfunction and leukocyte infiltration in vitro; 2) to ascertain whether Mfge8 and its molecular domains stimulates cultured VSMC proliferation/migration and MMP activities; 3) to determine the molecular domains of Mfge8 responsible for the enhanced neointimal formation in a mouse model of vascular remodeling. These results will help us to understand the molecular mechanisms by which Mfge8 regulates the vascular remodeling, and could lead to the development of a pharmacological intervention to decelerate the pathological process of vascular diseases in the future.

Project ID:PC10301-0311
External Project ID:NSC102-2320-B182-007-MY3