The heparin binding domain of von Willebrand factor binds to growth factors and promotes angiogenesis in wound healing
File(s)
Author(s)
Type
Journal Article
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.
Date Issued
2019-06-13
Date Acceptance
2019-04-04
Citation
Blood, 2019, 133 (24), pp.2559-2569
ISSN
0006-4971
Publisher
American Society of Hematology
Start Page
2559
End Page
2569
Journal / Book Title
Blood
Volume
133
Issue
24
Copyright Statement
© 2019 by The American Society of Hematology
Sponsor
Medical Research Council (MRC)
British Heart Foundation
British Heart Foundation
British Heart Foundation
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000471256200004&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
G0600868
PG/16/91/32515
FS/10/47/28393
PG/11/50/28984
Subjects
Science & Technology
Life Sciences & Biomedicine
Hematology
A1 DOMAIN
DISEASE
VWF
LOCALIZATION
FIBRONECTIN
MODEL
Publication Status
Published
Date Publish Online
2019-06-13