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

DOI

10.2991/artres.k.201209.044How to use a DOI?

Keywords

VWF; VSMC; αvβ3; LRP4

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 low-density 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_vβ₃ signaling. The decreased IH following vascular injury suggests that targeting VWF-LRP4 interactions may contribute to limit remodeling.

Copyright

© 2020 Association for Research into Arterial Structure and Physiology. Publishing services by Atlantis Press International B.V.

Open Access

This is an open access article distributed under the CC BY-NC 4.0 license (http://creativecommons.org/licenses/by-nc/4.0/).

TY  - JOUR
AU  - Cécile V. Denis
AU  - Patrick Lacolley
AU  - Jeremy Lagrange
AU  - Peter J. Lenting
AU  - Jean-Baptiste Michel
AU  - Alexandre Raoul
AU  - Veronique Regnault
PY  - 2020
DA  - 2020/12/31
TI  - P.31 Von Willebrand Factor Induces Vascular Smooth Muscle Cell Proliferation and Migration Through Low Density Lipoprotein-Related Receptor Protein 4 and αvβ3 Integrin
JO  - Artery Research
SP  - S54
EP  - S54
VL  - 26
IS  - Supplement 1
SN  - 1876-4401
UR  - https://doi.org/10.2991/artres.k.201209.044
DO  - 10.2991/artres.k.201209.044
ID  - Denis2020
ER  -