Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca2+ Levels and eNOS Phosphorylation at Ser1179

Pharmaceuticals

Stéphanie Thebault¹  Carmen González¹  Celina Garc໚¹  David Arredondo Zamarripa¹  Gabriel Nava¹  Luis Vaca²  Fernando López-Casillas²  Gonzalo Martínez de la Escalera¹ 

[1] Instituto de Neurobiología, Universidad Nacional Autónoma de México (UNAM), Campus UNAM-Juriquilla, Querétaro 76230, Mexico; E-Mails:;Instituto de Fisiología Celular, Universidad Nacional Autónoma de México (UNAM), Ciudad Universitaria, Del. Coyoacán, México, D.F., 04510, Mexico; E-Mails:

关键词: vasoinhibins;    16kDa-prolactin;    bradykinin;    endothelial nitric oxide synthase;    calcium mobilization;    transient receptor potential channels;   

DOI  :  10.3390/ph4071052

来源: mdpi

【 摘 要 】

Vasoinhibins, a family of antiangiogenic peptides derived from prolactin proteolysis, inhibit the vascular effects of several proangiogenic factors, including bradykinin (BK). Here, we report that vasoinhibins block the BK-induced proliferation of bovine umbilical vein endothelial cells. This effect is mediated by the inactivation of endothelial nitric oxide synthase (eNOS), as the NO donor DETA-NONOate reverted vasoinhibin action. It is an experimentally proven fact that the elevation of intracellular Ca²⁺ levels ([Ca²⁺]_i) upon BK stimulation activates eNOS, and vasoinhibins blocked the BK-mediated activation of phospholipase C and the formation of inositol 1,4,5-triphosphate leading to a reduced release of Ca²⁺ from intracellular stores. The [Ca²⁺]_i rise evoked by BK also involves the influx of extracellular Ca²⁺ via canonical transient receptor potential (TRPC) channels. Vasoinhibins likely interfere with TRPC-mediated Ca²⁺ entry since La³⁺, which is an enhancer of TRPC4 and TRPC5 channel activity, prevented vasoinhibins from blocking the stimulation by BK of endothelial cell NO production and proliferation, and vasoinhibins reduced the BK-induced increase of TRPC5 mRNA expression. Finally, vasoinhibins prevented the BK-induced phosphorylation of eNOS at Ser¹¹⁷⁹, a post-translational modification that facilitates Ca²⁺-calmodulin activation of eNOS. Together, our data show that vasoinhibins, by lowering NO production through the inhibition of both [Ca²⁺]_i mobilization and eNOS phosphorylation, prevent the BK-induced stimulation of endothelial cell proliferation. Thus, vasoinhibins help to regulate BK effects on angiogenesis and vascular homeostasis.

【 授权许可】

CC BY   
© 2011 by the authors; licensee MDPI, Basel, Switzerland.