P.31 Von Willebrand Factor Induces Vascular Smooth Muscle Cell Proliferation and Migration Through Low Density Lipoprotein-Related Receptor Protein 4 and αvβ3 Integrin

Abstract

Background and Objectives

Von Willebrand factor (VWF) is a plasma glycoprotein involved in primary hemostasis but recent data suggest additional roles beyond hemostasis in angiogenesis and potentially in vascular smooth muscle cell (VSMC) proliferation. Our aim was to investigate how VWF can modulate VSMC proliferation and identified the underlying mechanisms and the in vivo pathophysiological relevance.

Methods and Results

Cultured aortic VSMCs proliferation and migration were increased in the presence of VWF. VSMCs treatment with a siRNA targeting α_v integrin or the RGT-peptide blocking α_vβ₃ signaling completely inhibited proliferation. VWF did not bind directly to α_vβ₃ on VSMCs. We identified that VWF A2 domain was able to bind VSMCs. Since the lowdensity lipoprotein-related receptor protein (LRP) family are known to act as co-receptors we hypothesized the involvement of a member in the signaling pathway. Using the universal LRP-inhibitor (RAP), we confirmed LRP-mediated VSMC proliferation. siRNA experiments and proximity ligation assay staining identified LRP4 as the VWF-counterreceptor on VSMCs and showed co-localization between α_vβ₃ and LRP4. Carotid ligations were applied to VWF +/+ and −/− mice and intimal hyperplasia (IH) was measured. Less VWF−/− mice developed IH compared to VWF +/+ mice. Finally the proliferative effect of VWF was confirmed in human atherosclerotic lesions from different vessels (aortas, carotids) showing a proximity between VWF and a-SM actin positive cells.

Conclusions

VWF mediates VSMC proliferation through its A2 domain binding to the LRP4 receptor and integrin α_vβ₃signaling. The decreased IH following vascular injury suggests that targeting VWF-LRP4 interactions may contribute to limit remodeling.