β2-Glycoprotein I Inhibits Vascular Endothelial Growth Factor-Induced Angiogenesis by Suppressing the Phosphorylation of Extracellular Signal-Regulated Kinase 1/2, Akt, and Endothelial Nitric Oxide Synthase

Angiogenesis is the process of new blood vessel formation, and it plays a key role in various physiological and pathological conditions. The beta(2)-glycoprotein I (beta(2)-GPI) is a plasma glycoprotein with multiple biological functions, some of which remain to be elucidated. This study aimed to identify the contribution of beta(2)-GPI on the angiogenesis induced by vascular endothelial growth factor (VEGF), a pro-angiogenic factor that may regulate endothelial remodeling, and its underlying mechanism. Our results revealed that beta(2)-GPI dose-dependently decreased the VEGF-induced increase in endothelial cell proliferation, using the 3-(4,5-dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) and the bromodeoxyuridine (BrdU) incorporation assays. Furthermore, incubation with both beta(2)-GPI and deglycosylated beta(2)-GPI inhibited the VEGF-induced tube formation. Our results suggest that the carbohydrate residues of beta(2)-GPI do not participate in the function of anti-angiogenesis. Using in vivo Matrigel plug and angioreactor assays, we show that beta(2)-GPI remarkably inhibited the VEGF-induced angiogenesis at a physiological concentration. Moreover, beta(2)-GPI inhibited the VEGF-induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), Akt, and endothelial nitric oxide synthase (eNOS). In summary, our in vitro and in vivo data reveal for the first time that beta(2)-GPI inhibits the VEGF-induced angiogenesis and highlights the potential for beta(2)-GPI in anti-angiogenic therapy.