Vascular endothelial growth factor–stimulated endothelial cells promote adhesion and activation of platelets

Abstract

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, αIIbβ3, 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 αIIbβ3 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.

Platelets in cancer metastasis: To help the “villain” to do evil

“…[102][103][104] Endothelial cells in tumorous vessels have an elevated expression of tissue factor, 105,106 which enhances thrombin generation and subsequent platelet activation and deposition within tumor vasculature. 106,107 Therefore, platelets are often present as adhered platelets, platelet aggregates and/or micro-thrombi in tumor vessels. 60,106 Angiogenic mediators, such as VEGF, released by these activated platelets, in turn, enhance endothelial activation and proliferation, and thus angiogenesis.…”

Selective NTPDase2 expression modulates in vivo rat glioma growth

“…Importantly, these events all play a crucial role in tumorigenesis. (4,(22)(23)(24) Involvement of ADP-activated platelets in the malignity of gliomas expressing NTPDase2. Considering ADP is an important platelet activator, we tested whether platelet recruitment may contribute to the increased malignity of C6-EYFP/NTPDase2-derived gliomas.…”

In vitrobasic fibroblast growth factor (bFGF) delivery using an antithrombogenic 2‐methacryloyloxyethyl phosphorylcholine (MPC) polymer coated with a micropatterned diamond‐like carbon (DLC) film

“…29 Verheul et al also demonstrated that bFGF did not stimulate the platelet adhesion and activation. 30 Biomaterials developed in this research not only had passive biocompatibility that would properly fit in the living body without being excluded from the living bodies, but also conversely, possessed biological properties effectively acting on living bodies.…”