Special Issue "Angiogenesis Inhibitors"

Affiliation: Department of Surgery, Umeå University, 90185 Umeå, Sweden; E-Mail: malin.sund@surgery.umu.se
Abstract: Endogenous inhibitors of angiogenesis are proteins or fragments of proteins that are formed in the body, which subsequently can inhibit the angiogenic process. These substances can be found both in the circulation and sequestered in the extracellular matrix (ECM) surrounding cells. Many matrix-derived inhibitors of angiogenesis, such as endostatin, tumstatin, canstatin and arresten, are bio-active fragments of larger ECM molecules. These substances become released upon proteolysis of the ECM and the vascular basement membrane (VBM) by enzymes of the tumor microenvironment. Although the role of matrix-derived angiogenesis inhibitors is well studied in animal models of cancer, their role in human cancers is less established. We will in this review discuss the current knowledge about these substances and the potential use of them as tumor therapeutics and/or biomarkers.

Type of Paper: Article
Title: Vasoinhibins and Endothelial Cell Proliferation
Authors: Stéphanie Thebault ¹, Carmen González ¹, Celina García¹, David Arredondo Zamarripa ¹, Gabriel Nava ¹, Luis Vaca ², Gonzalo Martínez de la Escalera ¹ and Carmen Clapp ¹
Affiliations: ¹ Instituto de Neurobiología, Universidad Nacional Autónoma de México, Querétaro, Querétaro, 76230, México
² Departamento de Biología Celular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, Del. Coyoacán, 04510 México, D.F., México; E-Mails: clapp@servidor.unam.mx (C.C.); stephaniethebault@gmail.com (S.T.)
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.
Inactivation of endothelial nitric oxide synthase (eNOS) mediates this effect, as the NO donor DETA-NONOate prevented vasoinhibin action. Normally, the increase 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 transient receptor potential canonical (TRPC) channels. Vasoinhibins likely interfere with TRPC-mediated Ca²⁺ entry, since La(3+), an enhancer of TRPC4 and TRPC5 channel activity, prevented vasoinhibins from blocking the stimulation by BK of 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. These mechanisms may help to regulate BK effects on angiogenesis and vascular homeostasis.