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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

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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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Figure 6

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Vasohibin suppresses tumor growth and tumor angiogenesis. (A) The synthe...
Vasohibin suppresses tumor growth and tumor angiogenesis. (A) The synthesis of vasohibin protein in LLC cells. Cell extracts were prepared from mock or vasohibin transfectants (Vh-bulk) for Western blotting. Clone 16 and clone 19 were vasohibin-producing clones. (B) Effect of vasohibin on the proliferation of LLC cells in vitro. Proliferation of mock transfectants, vasohibin transfectants, clone 16, and clone 19 was determined. (C) Effect of secreted vasohibin from LLC cells on the migration of HUVECs. Mock or vasohibin transfectants were plated on the lower compartment of a modified Boyden chamber and the migration of HUVECs toward the lower chamber of the Transwell insert was analyzed. Values are expressed as mean ± SD of 4 samples. (D) Effect of vasohibin gene transfection on the growth of LLC cells in vivo. BDF1 mice were inoculated intradermally with LLC cells. Tumor volume was determined consecutively. (E) Effect of vasohibin gene transfection on tumor angiogenesis. Paraffin sections were prepared from tumors for the immunostaining of CD31; sections obtained on day 8 after inoculation are shown. Visualization with a DAKO LSAB+/HRP kit is shown at left, and that with streptavidin-Cy3 conjugate on the right. Yellow lines trace vascular lumens. Scale bars: 50 μm. (F) Quantitative analysis of tumor vascular area. Total vascular area per field was determined using NIH Image and compared. Values are expressed as mean ± SD of 6 random fields. *P < 0.05; **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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