Milk fat globule epidermal growth factor VIII signaling in arterial wall remodeling

Abstract

Arterial inflammation and remodeling, important sequellae of advancing age, are linked to the pathogenesis of age-associated arterial diseases e.g. hypertension, atherosclerosis, and metabolic disorders. Recently, high-throughput proteomic screening has identified milk fat globule epidermal growth factor VIII (MFG-E8) as a novel local biomarker for aging arterial walls. Additional studies have shown that MFG-E8 is also an element of the arterial inflammatory signaling network. The transcription, translation, and signaling levels of MFG-E8 are increased in aged, atherosclerotic, hypertensive, and diabetic arterial walls in vivo as well as activated vascular smooth muscle cells (VSMC) and a subset of macrophages in vitro. In VSMC, MFG-E8 increases proliferation and invasion as well as the secretion of inflammatory molecules. In endothelial cells (EC), MFG-E8 facilitates apoptosis. In addition, MFG-E8 has been found to be an essential component of the endothelial-derived microparticles that relay biosignals and modulate arterial wall phenotypes. This review mainly focuses upon the landscape of MFG-E8 expression and signaling in adverse arterial remodeling. Recent discoveries have suggested that MFG-E8 associated interventions are novel approaches for the retardation of the enhanced rates of VSMC proliferation and EC apoptosis that accompany arterial wall inflammation and remodeling during aging and age-associated arterial disease.

Figure 1

Schematic depicting the structure of MFG-E8. EGF: epidermal growth factor domain; C1 and C2: discoid domains or coagulation factor V or VIII-homologous domains. PT: proline/threonine-enrich motif.

Figure 2

MGF-E8 protein within the aortic wall in rats (A), monkeys (B), and humans (C). From Fu Z et al [14].

Figure 3

Diagram of a diverse role for MFG-E8 in vascular cells.

Figure 4

Diagram of multiple roles for microparticles in the arterial wall.