Crucial role of activin a in tubulogenesis of endothelial cells induced by vascular endothelial growth factor.
The present study was conducted to elucidate the role of activin A in tubulogenesis of vascular endothelial cells. Activin A was produced in bovine aortic endothelial cells (BAEC). These cells also expressed the type I and type II activin receptors. When added to BAEC cultured in a collagen gel, activin A induced capillary formation. Activin A was as potent as vascular endothelial growth factor (VEGF) and markedly enhanced VEGF-induced tubulogenesis. To examine the role of endogenous activin A, we added follistatin, an inhibitor of activin A. Follistatin nearly completely blocked the VEGF-induced tubulogenesis, and the effect of follistatin was reproduced by transfection of the dominant-negative type II activin receptor gene. In BAEC, activin A increased the expression of VEGF and the VEGF receptors, Flt-1 and Flk-1. On the other hand, VEGF increased the production of activin A. Finally, addition of follistatin, which blocks the action of endogenous activin A, reduced the expression of Flt-1 and Flk-1. These results indicate that an autocrine factor activin A amplifies the effect of VEGF by up-regulating VEGF and its receptors. This effect of activin A is critical in the VEGF-induced tubulogenic morphogenesis in BAEC.
Maeshima
Kyoko
K
Institute for Molecular & Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
Maeshima
Akito
A
Hayashi
Yoshiro
Y
Kishi
Shoji
S
Kojima
Itaru
I
D029404:Activin Receptors / Q000235:genetics; D028341:Activins / Q000502:physiology*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000502:physiology*; D016326:Extracellular Matrix Proteins / Q000235:genetics; D038681:Follistatin / Q000494:pharmacology; D006801:Humans; D028322:Inhibin-beta Subunits / Q000502:physiology*; D018919:Neovascularization, Physiologic; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000494:pharmacology*; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics
D016326:Extracellular Matrix Proteins; D038681:Follistatin; D042461:Vascular Endothelial Growth Factor A; C422405:activin A; D028341:Activins; D028322:Inhibin-beta Subunits; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D029404:Activin Receptors