Endothelial von Willebrand factor regulates angiogenesis.
The regulation of blood vessel formation is of fundamental importance to many physiological processes, and angiogenesis is a major area for novel therapeutic approaches to diseases from ischemia to cancer. A poorly understood clinical manifestation of pathological angiogenesis is angiodysplasia, vascular malformations that cause severe gastrointestinal bleeding. Angiodysplasia can be associated with von Willebrand disease (VWD), the most common bleeding disorder in man. VWD is caused by a defect or deficiency in von Willebrand factor (VWF), a glycoprotein essential for normal hemostasis that is involved in inflammation. We hypothesized that VWF regulates angiogenesis. Inhibition of VWF expression by short interfering RNA (siRNA) in endothelial cells (ECs) caused increased in vitro angiogenesis and increased vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2)-dependent proliferation and migration, coupled to decreased integrin αvβ3 levels and increased angiopoietin (Ang)-2 release. ECs expanded from blood-derived endothelial progenitor cells of VWD patients confirmed these results. Finally, 2 different approaches, in situ and in vivo, showed increased vascularization in VWF-deficient mice. We therefore identify a new function of VWF in ECs, which confirms VWF as a protein with multiple vascular roles and defines a novel link between hemostasis and angiogenesis. These results may have important consequences for the management of VWD, with potential therapeutic implications for vascular diseases.
Cardiovascular Sciences, National Heart and Lung Institute, Faculty of Medicine, Hammersmith Campus, Imperial College Academic Health Sciences Centre, Imperial College London, London, UK.
Richard D
RD
Starke
Francesco
F
Ferraro
Koralia E
KE
Paschalaki
Nicola H
NH
Dryden
Thomas A J
TA
McKinnon
Rachel E
RE
Sutton
Elspeth M
EM
Payne
Dorian O
DO
Haskard
Alun D
AD
Hughes
Daniel F
DF
Cutler
Mike A
MA
Laffan
Anna M
AM
Randi
D000328:Adult; D000369:Aged, 80 and over; D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D005260:Female; D006487:Hemostasis; D006801:Humans; D015151:Immunoblotting; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics / Q000378:metabolism; D014842:von Willebrand Diseases / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism*
D042702:Angiopoietin-2; D039302:Integrin alphaVbeta3; D014841:von Willebrand Factor; D040301:Vascular Endothelial Growth Factor Receptor-2