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Blood, 15 December 2000, Vol. 96, No. 13, pp. 4216-4221
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Vascular endothelial growth factor-stimulated endothelial cells
promote adhesion and activation of platelets
Henk M. W. Verheul,
Anita
S. Jorna,
Klaas Hoekman,
Henk J. Broxterman,
Martijn F. B. G. Gebbink, and
Herbert M. Pinedo
From the Department of Medical Oncology, University
Hospital "Vrije Universiteit," 1007 MB Amsterdam, The Netherlands,
and the Department of Internal Medicine, University Medical Center
Utrecht, Utrecht, The Netherlands.
Coagulation abnormalities, including an increased platelet
turnover, are frequently found in patients with cancer. Because platelets secrete angiogenic factors on activation, this study tested
the hypothesis that platelets contribute to angiogenesis. Stimulation
with vascular endothelial growth factor (VEGF, 25 ng/mL) of human
umbilical vein endothelial cells (HUVECs) promoted adhesion of
nonactivated platelets 2.5-fold. In contrast, stimulation of HUVECs
with basic fibroblast growth factor (bFGF) did not promote platelet
adhesion. By blocking tissue factor (TF) activity, platelet adhesion
was prevented and antibodies against fibrin(ogen) and the
platelet-specific integrin,  IIb 3,
inhibited platelet adhesion for 70% to 90%. These results indicate
that VEGF-induced platelet adhesion to endothelial cells is dependent
on activation of TF. The involvement of fibrin(ogen) and the
IIb3 integrin, which exposes a
high-affinity binding site for fibrin(ogen) on platelet activation,
indicates that these adhering platelets are activated. This was
supported by the finding that the activity of thrombin, a product of
TF-activated coagulation and a potent platelet activator, was required
for platelet adhesion. Finally, platelets at physiologic concentrations
stimulated proliferation of HUVECs, indicative of proangiogenic
activity in vivo. These results support the hypothesis that platelets
contribute to tumor-induced angiogenesis. In addition, they may explain
the clinical observation of an increased platelet turnover in cancer
patients. Platelets may also play an important role in other
angiogenesis-dependent diseases in which VEGF is involved, such as
diabetes and autoimmune diseases.
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