Pharmaceuticals 2011, 4(7), 1052-1069; doi:10.3390/ph4071052
Article

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

Received: 29 April 2011; in revised form: 6 July 2011 / Accepted: 19 July 2011 / Published: 20 July 2011
(This article belongs to the Special Issue Angiogenesis Inhibitors)
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract: 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.
Keywords: vasoinhibins; 16kDa-prolactin; bradykinin; endothelial nitric oxide synthase; calcium mobilization; transient receptor potential channels
PDF Full-text Download PDF Full-Text [476 KB, uploaded 20 July 2011 14:21 CEST]

Export to BibTeX |
EndNote


MDPI and ACS Style

Thebault, S.; González, C.; García, C.; Zamarripa, D.A.; Nava, G.; Vaca, L.; López-Casillas, F.; De la Escalera, G.M.; Clapp, C. Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca2+ Levels and eNOS Phosphorylation at Ser1179. Pharmaceuticals 2011, 4, 1052-1069.

AMA Style

Thebault S, González C, García C, Zamarripa DA, Nava G, Vaca L, López-Casillas F, De la Escalera GM, Clapp C. Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca2+ Levels and eNOS Phosphorylation at Ser1179. Pharmaceuticals. 2011; 4(7):1052-1069.

Chicago/Turabian Style

Thebault, Stéphanie; González, Carmen; García, Celina; Zamarripa, David Arredondo; Nava, Gabriel; Vaca, Luis; López-Casillas, Fernando; De la Escalera, Gonzalo Martínez; Clapp, Carmen. 2011. "Vasoinhibins Prevent Bradykinin-Stimulated Endothelial Cell Proliferation by Inactivating eNOS via Reduction of both Intracellular Ca2+ Levels and eNOS Phosphorylation at Ser1179." Pharmaceuticals 4, no. 7: 1052-1069.

Pharmaceuticals EISSN 1424-8247 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert