Platelet-mediated angiogenesis is independent of VEGF and fully inhibited by aspirin

ETULAIN J; FONDEVILA C; NEGROTTO S; SCHATTNER M

British Journal of Pharmacology

Wiley Online Library

Año: 2013

1476-5381

Background & Purpose: Platelets are major players in every step of vessel development through the local delivery of angiogenesis-modulating factors, including the proangiogenic vascular endothelial growth factor (VEGF) and the antiangiogenic endostatin. Although thrombin is the most potent agonist and is highly elevated in angiogenesis-related diseases, studies regarding its action on the release of platelet angiogenic factors are scarce and controversial. Herein, we have investigated the role of thrombin not only in VEGF and endostatin release but also in the net platelet angiogenic activity. Experimental Approach: Human platelets were stimulated with thrombin in the presence of inhibitors of signaling pathways involved in platelet activation and supernatants/releasates were used to determine the levels of angiogenic molecules and to induce angiogenic responses. Key Results: We found that thrombin induced the secretion of both VEGF and endostatin; however, the overall effect of the releasates was proangiogenic as they promoted tubule like formation and increased the endothelial proliferation. Both responses were only slightly suppressed in the presence of a VEGF receptor-neutralizing antibody. Pharmacological studies revealed that while inhibitors of PKC, p38, ERK1/2, Src kinases, or PI3K/Akt exerted only partial inhibitory effects, aspirin fully blocked the proangiogenic activity. Conclusions & Implications: In contrast to current belief, platelet proangiogenic responses are independent of VEGF and appear to be the result of the combined action of several molecules. Moreover, our data reinforce the notion that aspirin could be a promising therapeutic agent to treat angiogenesis-related diseases.