Overexpression of von Willebrand factor is an independent risk factor for pathogenesis of intimal hyperplasia: preliminary studies.
OBJECTIVE
Deposition of von Willebrand factor (vWF) is increased in hyperplastic intima of grafts, vWF levels are elevated in patients with cardiovascular diseases, and there is resistance to progression of atherosclerosis in pigs with von Willebrand disease. We hypothesize that increased expression of endothelial vWF has mitogenic effects on smooth muscle cell (SMC) proliferation.


METHODS
In an in vitro study, mouse aortic smooth muscle cells (SMC) were exposed to vWF in various concentrations (0, 5, 20, 100, 500, and 1000 ng/mL). DNA synthesis of SMC was measured with (3)H-thymidine incorporation. In an in vivo study, 108 mice from inbred strains of C57BL/6J (control) and RIIIS/J (characteristic of low plasma vWF) underwent carotid artery ligation (flow cessation model) and were divided into three groups: C57BL/6J, RIIIS/J, and RIIIS/J treated with desmopressin (DDAVP; intraperitoneal injection at 3 micro g/kg/d). At 2 and 4 weeks, carotid arteries were harvested for analysis with immunohistochemical analysis, morphometric studies, and reverse transcriptase polymerase chain reaction; plasma vWF was measured with an enzyme-linked immunosorbent assay.


RESULTS
In vitro SMC proliferation showed a positive dose-response curve with vWF stimulation. Intimal hyperplasia (IH) in carotid arteries was prominent in C57BL/6J mice, absent in RIIIS/J mice, and moderate in RIIIS/J treated with DDAVP (intima-media ratio, 71% +/- 18%, 0, and 32% +/- 12%, respectively; P <.01). vWF deposition occurred in all hyperplastic intima subjacent to intact endothelium. Plasma vWF correlated with degree of IH (110% +/- 10%, 21% +/- 7%, and 45% +/- 8%, respectively; P <.05). vWF-messenger RNA was 9 times higher in carotid arteries of C57BL/6J mice and 4 times higher in RIIIS/J with DDAVP, compared with RIIIS/J.


CONCLUSIONS
vWF directly stimulates SMC proliferation in vitro via a direct dose-response effect. In vivo low shear stress accelerates IH proportional to vWF expression. This could occur under intact endothelium without platelet activation and platelet-derived growth factor release. In effect, control of IH may entail modulation of vWF expression.
Qin
Feng
F
Section of Vascular Surgery and the Heart and Vascular Institute of New Jersey, Englewood Hospital and Medical Center, Englewood, New Jersey 07631, USA.
Impeduglia
Theresa
T
Schaffer
Pamela
P
Dardik
Herbert
H
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics*; D006965:Hyperplasia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D012307:Risk Factors; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology*; D014841:von Willebrand Factor / Q000008:administration & dosage / Q000235:genetics* / Q000494:pharmacology
D014841:von Willebrand Factor