The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing

Abstract

During wound healing, the distribution, availability, and signaling of growth factors (GFs) are orchestrated by their binding to extracellular matrix components in the wound microenvironment. Extracellular matrix proteins have been shown to modulate angiogenesis and promote wound healing through GF binding. The hemostatic protein von Willebrand factor (VWF) released by endothelial cells (ECs) in plasma and in the subendothelial matrix has been shown to regulate angiogenesis; this function is relevant to patients in whom VWF deficiency or dysfunction is associated with vascular malformations. Here, we show that VWF deficiency in mice causes delayed wound healing accompanied by decreased angiogenesis and decreased amounts of angiogenic GFs in the wound. We show that in vitro VWF binds to several GFs, including vascular endothelial growth factor-A (VEGF-A) isoforms and platelet-derived growth factor-BB (PDGF-BB), mainly through the heparin-binding domain (HBD) within the VWF A1 domain. VWF also binds to VEGF-A and fibroblast growth factor-2 (FGF-2) in human plasma and colocalizes with VEGF-A in ECs. Incorporation of the VWF A1 HBD into fibrin matrices enables sequestration and slow release of incorporated GFs. In vivo, VWF A1 HBD-functionalized fibrin matrices increased angiogenesis and GF retention in VWF-deficient mice. Treatment of chronic skin wounds in diabetic mice with VEGF-A165 and PDGF-BB incorporated within VWF A1 HBD-functionalized fibrin matrices accelerated wound healing, with increased angiogenesis and smooth muscle cell proliferation. Therefore, the VWF A1 HBD can function as a GF reservoir, leading to effective angiogenesis and tissue regeneration.

Systemically Administered, Target-specific, Multi-functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…In line with the syndecan-binding domain enhancing growth factor signaling, it has been reported that the use of locally applied, fibrin-conjugated peptides with heparin binding domains enhance wound healing [72,73] . The authors attributed the beneficial effects of the biomaterial on would healing on growth factor retention in the wounds by binding to the heparin-binding domain [72,73] . On the other hand, it was recently demonstrated that some of the heparin-binding growth factors bound too strongly to the HSPGs in the ECM, i.e.…”

Systemically Administered, Target-Specific, Multi-Functional Therapeutic Recombinant Proteins in Regenerative Medicine

“…syndecan-binding domain, to growth factors induces tonic growth factor signaling [73]. In line with the syndecan-binding domain enhancing growth factor signaling, it has been reported that the use of locally applied, fibrin-conjugated peptides with heparin binding domains enhances wound healing [74,75]. The authors attributed the beneficial effects of the biomaterial on would healing on growth factor retention in the wounds by binding to the heparin-binding domain [74,75].…”

Von Willebrand factor and cancer; metastasis and coagulopathies

“…Paradoxically, in a hind limb ischemia model, VWF ‐/‐ mice displayed reduced arteriogenesis and angiogenesis, which gives rise to impaired blood flow recovery in these animals 60 . More recently, in the context of wound healing, circulating VWF has been shown to bind directly to a number of growth factors including several pro‐angiogenic factors (platelet‐derived growth factor [PDGF], VEGF, and fibroblast growth factor [FGF] families) and mediate their localized delivery at sites of tissue damage to promote angiogenesis and repair 12 . Accordingly, VWF ‐/‐ mice demonstrated impaired angiogenesis and delayed wound healing, compared to wild type mice.…”