Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis
Kazuhide Watanabe, … , Hikaru Sonoda, Yasufumi Sato
Kazuhide Watanabe, … , Hikaru Sonoda, Yasufumi Sato
Published October 1, 2004
Citation Information: J Clin Invest. 2004;114(7):898-907. https://doi.org/10.1172/JCI21152.
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Article Angiogenesis

Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis

Abstract

Negative feedback is a crucial physiological regulatory mechanism, but no such regulator of angiogenesis has been established. Here we report a novel angiogenesis inhibitor that is induced in endothelial cells (ECs) by angiogenic factors and inhibits angiogenesis in an autocrine manner. We have performed cDNA microarray analysis to survey VEGF-inducible genes in human ECs. We characterized one such gene, KIAA1036, whose function had been uncharacterized. The recombinant protein inhibited migration, proliferation, and network formation by ECs as well as angiogenesis in vivo. This inhibitory effect was selective to ECs, as the protein did not affect the migration of smooth muscle cells or fibroblasts. Specific elimination of the expression of KIAA1036 in ECs restored their responsiveness to a higher concentration of VEGF. The expression of KIAA1036 was selective to ECs, and hypoxia or TNF-α abrogated its inducible expression. As this molecule is preferentially expressed in ECs, we designated it “vasohibin.” Transfection of Lewis lung carcinoma cells with the vasohibin gene did not affect the proliferation of cancer cells in vitro, but did inhibit tumor growth and tumor angiogenesis in vivo. We propose vasohibin to be an endothelium-derived negative feedback regulator of angiogenesis.

Authors

Kazuhide Watanabe, Yasuhiro Hasegawa, Hiroshi Yamashita, Kazue Shimizu, Yuanying Ding, Mayumi Abe, Hideki Ohta, Keiichi Imagawa, Kanji Hojo, Hideo Maki, Hikaru Sonoda, Yasufumi Sato

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KIAA1036 may act as a negative feedback regulator. (A) Effect of KIAA103...
KIAA1036 may act as a negative feedback regulator. (A) Effect of KIAA1036 on the migration of HUVECs. Migration of HUVECs was analyzed as described in Methods. The indicated concentrations of growth factors and/or KIAA1036 protein were placed in the lower chamber of the Transwell insert. Values are expressed as mean ± SD of 4 samples. (B) Effect of KIAA1036 on the migration of HASMCs or fibroblasts. Migration of HASMCs or fibroblasts was analyzed as described in Methods. The indicated combinations of PDGF, FGF-2, and KIAA1036 protein were placed in the lower chamber. Values are expressed as mean ± SD of 4 samples. (C) Bell-shaped pattern of the VEGF-stimulated migration of HUVECs. The indicated concentrations of VEGF were placed in the lower chamber and HUVECs were plated in the upper chamber. Values are expressed as mean ± SD of 4 samples. (D) Selective downregulation of KIAA1036 synthesis. HUVECs were incubated for 4 hours with 500 nM synthetic phosphorothioate ODNs or vehicle alone. Thereafter, HUVECs were stimulated with VEGF (1 nM) for 24 hours, and Western blotting for KIAA1036 was performed. AS, AS-ODN; S, S-ODN; Scr, Scr-ODN; v, vehicle. (E) Modulation of the bell-shaped pattern of the VEGF effect by KIAA1036 AS-ODNs. HUVECs were incubated for 4 hours with 500 nM phosphorothioate ODNs. Thereafter, HUVECs were subjected to the migration assay described above. Values are expressed as mean ± SD of 4 samples. *P < 0.05, **P < 0.01.