P.31 Von Willebrand Factor Induces Vascular Smooth Muscle Cell Proliferation and Migration Through Low Density Lipoprotein-Related Receptor Protein 4 and αvβ3 Integrin
- 10.2991/artres.k.201209.044How to use a DOI?
- VWF; VSMC; αvβ3; LRP4
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.
- © 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
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 -