Artery Research

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Volume 26, Issue Supplement 1, December 2020, Pages S54 - S54

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

Authors
Cécile V. Denis3, Patrick Lacolley1, Jeremy Lagrange1, *, Peter J. Lenting3, Jean-Baptiste Michel2, Alexandre Raoul1, Veronique Regnault1
1INSERM, UMR_S 1116, Université de Lorraine, DCAC
2INSERM, UMR_S 1148- LVTS, Université de Paris
3HITh, UMR_S1176, INSERM, Université Paris-Saclay
*Corresponding author. Email: jeremy.lagrange@inserm.fr
Corresponding Author
Jeremy Lagrange
Available Online 31 December 2020.
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 αv integrin or the RGT-peptide blocking αvβ3 signaling completely inhibited proliferation. VWF did not bind directly to αvβ3 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 αvβ3 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 αvβ3 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/).

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<Previous Article In Issue
Next Article In Issue>
Journal
Artery Research
Volume-Issue
26 - Supplement 1
Pages
S54 - S54
Publication Date
2020/12/31
ISSN (Online)
1876-4401
ISSN (Print)
1872-9312
DOI
10.2991/artres.k.201209.044How to use a DOI?
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/).

Cite this article

risenwbib
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  -