| First Author | Lagrange J | Year | 2022 |
| Journal | Cardiovasc Res | Volume | 118 |
| Issue | 2 | Pages | 622-637 |
| PubMed ID | 33576766 | Mgi Jnum | J:330362 |
| Mgi Id | MGI:6717225 | Doi | 10.1093/cvr/cvab042 |
| Citation | Lagrange J, et al. (2021) The VWF/LRP4/alphaVbeta3-axis represents a novel pathway regulating proliferation of human vascular smooth muscle cells. Cardiovasc Res |
| abstractText | 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 alphav integrin or the RGT-peptide blocking alphavbeta3 signaling abolished proliferation. However, VWF did not bind to alphavbeta3 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 alphavbeta3 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 alphavbeta3 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 alphaVbeta3, thereby inducing VSMC proliferation. Interfering with A2-domain/LRP4 interactions might offer innovative and additional therapeutical approaches to limit pathological hyperplasia. |
