Abstract 298: Microfibrillar Protein 4 is an Integrin avß3/5 Ligand Involved in Vascular Remodeling

Abstract

Arterial injury stimulates remodeling responses that, when overexuberant, leads to stenosis. This response is influenced by specific integrin signaling in vascular smooth muscle cells (VSMCs). Microfibrillar-associated protein 4 (MFAP4) is a matricellular integrin ligand localized to the vascular wall. We hypothesized that systemic MFAP4 (sMFAP4) associates to vascular remodeling processes and that MFAP4 enhances integrin dependent VSMC activation and vasculoproliferative disease-associated remodeling. We explored the hypotheses using a prospective human cohort with symptomatic obstructive peripheral arterial disease (PAD), VSMC culture studies, and produced MFAP4 deficient mice for studying neointima formation. We demonstrate that the highest tertile of sMFAP4 was significantly associated with primary patency after vascular reconstruction, and the overall need for vascular reconstruction and mortality in 343 PAD patients. MFAP4 mediated the adhesion, migration, and proliferation of VSMCs in an integrin αVβ3/5-dependent manner in vitro. These effects were inhibited by MFAP4-blocking antibodies. MFAP4-deficient mice displayed delayed neointimal formation when challenged with carotid artery ligation, but the compensatory outward remodeling of vessel diameter was reduced. In conclusion, sMFAP4 has the potential to serve as a systemic marker morbidity and mortality in PAD. MFAP4 regulates integrin αVβ3/5 signaling and pathological remodeling in vivo, and may have therapeutic implications in vasculoproliferative diseases.