The VWF/LRP4/αVβ3-axis represents a novel pathway regulating proliferation of human vascular smooth muscle cells

Autor: Paulette Legendre, Melusine Didelot, Jeremy Lagrange, Olivier D. Christophe, Vincent Muczynski, Morel E Worou, Cécile V. Denis, Guillaume Gauchotte, Patrick Lacolley, François Plénat, Alexandre Raoul, Peter J. Lenting, Véronique Regnault, Jean-Baptiste Michel, Marc-Damien Lourenco-Rodrigues
Přispěvatelé: Défaillance Cardiovasculaire Aiguë et Chronique (DCAC), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Université Paris-Saclay, Université de Lorraine (UL), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université de Lorraine (UL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut Carnot IFPEN Transports Energie, IFP Energies nouvelles (IFPEN), IFP Energies nouvelles (IFPEN)-IFP Energies nouvelles (IFPEN), Laboratoire des Interactions Ecotoxicologie, Biodiversité, Ecosystèmes (LIEBE), Université Paul Verlaine - Metz (UPVM)-Centre National de la Recherche Scientifique (CNRS), Service de Pathologie [CHRU Nancy], Denis, Cécile, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord
Rok vydání: 2021
Předmět:
[SDV.MHEP.HEM] Life Sciences [q-bio]/Human health and pathology/Hematology
Male
Vascular smooth muscle
Physiology
Angiogenesis
[SDV]Life Sciences [q-bio]
Proliferation
Cell
030204 cardiovascular system & hematology
Vascular biology
Muscle
Smooth
Vascular
0302 clinical medicine
Cell Movement
hemic and lymphatic diseases
Receptor
Cells
Cultured
Mice
Knockout
0303 health sciences
biology
Chemistry
[SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology
Hyperplasia
Plaque
Atherosclerotic
Cell biology
medicine.anatomical_structure
Smooth muscle cells
cardiovascular system
medicine.symptom
Cardiology and Cardiovascular Medicine
Haemostasis
Signal Transduction
Myocytes
Smooth Muscle
Integrin
Inflammation
03 medical and health sciences
Von Willebrand factor
Neointima
Physiology (medical)
von Willebrand Factor
medicine
Animals
LDL-Receptor Related Proteins
Cell Proliferation
030304 developmental biology
Vascular System Injuries
Atherosclerosis
Integrin alphaVbeta3
medicine.disease
Mice
Inbred C57BL
biology.protein
Carotid Artery Injuries
Zdroj: Cardiovascular Research
Cardiovascular Research, Oxford University Press (OUP), 2021, ⟨10.1093/cvr/cvab042⟩
Cardiovascular Research, Oxford University Press (OUP), 2022, 118 (2), pp.622-637. ⟨10.1093/cvr/cvab042⟩
Cardiovascular Research, 2022, 118 (2), pp.622-637. ⟨10.1093/cvr/cvab042⟩
ISSN: 1755-3245
0008-6363
DOI: 10.1093/cvr/cvab042
Popis: Aims Von Willebrand factor (VWF) is a plasma glycoprotein involved in primary hemostasis, while also having additional roles beyond hemostasis namely in cancer, inflammation, angiogenesis and potentially in vascular smooth muscle cell (VSMC) proliferation. Here, we addressed how VWF modulates VSMC proliferation and investigated the underlying molecular pathways and the in vivo pathophysiological relevance. Methods and results VWF induced proliferation of human aortic VSMCs and also promoted VSMC migration. Treatment of cells with a siRNA against αv integrin or the RGT-peptide blocking αvβ3 signaling abolished proliferation. However, VWF did not bind to αvβ3 on VSMCs through its RGD-motif. Rather, we identified the VWF A2 domain as the region mediating binding to the cells. We hypothesized the involvement of a member of the LDL-related receptor protein (LRP) family due to their known ability to act as co-receptors. Using the universal LRP-inhibitor receptor-associated protein, we confirmed LRP-mediated VSMC proliferation. siRNA experiments and confocal fluorescence microscopy identified LRP4 as the VWF-counterreceptor on VSMCs. Also co-localization between αvβ3 and LRP4 was observed via proximity ligation analysis and immuno-precipitation experiments. The pathophysiological relevance of our data was supported by VWF-deficient mice having significant reduced, if any, hyperplasia in carotid artery ligation and artery femoral denudation models. In wild-type mice, infiltration of VWF in intimal regions enriched in proliferating VSMCs was found. Interestingly, also analysis of human atherosclerotic lesions showed abundant VWF accumulation in VSMC-proliferating rich intimal areas. Conclusions VWF mediates VSMC proliferation through a mechanism involving A2 domain binding to the LRP4 receptor and integrin αvβ3 signaling. Our findings provide new insights into the mechanisms that drive physiological repair and pathological hyperplasia of the arterial vessel wall. In addition, the VWF/LRP4-axis may represent a novel therapeutic target to modulate VSMC proliferation. Translational perspective The mechanisms that drive physiological repair and pathological hyperplasia of the arterial vessel wall are complex and only partially understood. Specifically, the role of subendothelial-matrix proteins remains unclear. Here, we show that the hemostatic protein von Willebrand factor (VWF) accumulates in the vascular wall of atherosclerotic lesions and localizes to areas of vascular smooth muscle cell (VSMC) proliferation. VWF was found to use its A2-domain for binding to the VSMC-receptor LRP4, which in turn triggered outside-in signaling via integrin αVβ3, thereby inducing VSMC proliferation. Interfering with A2-domain/LRP4 interactions might offer innovative and additional therapeutical approaches to limit pathological hyperplasia.
Databáze: OpenAIRE
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