Vasohibin as an endothelium-derived negative feedback regulator of angiogenesis.
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-alpha 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.
Watanabe
Kazuhide
K
Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
Hasegawa
Yasuhiro
Y
Yamashita
Hiroshi
H
Shimizu
Kazue
K
Ding
Yuanying
Y
Abe
Mayumi
M
Ohta
Hideki
H
Imagawa
Keiichi
K
Hojo
Kanji
K
Maki
Hideo
H
Sonoda
Hikaru
H
Sato
Yasufumi
Y
D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D025461:Feedback, Physiological; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014018:Tissue Distribution; D042442:Vascular Endothelial Growth Factors / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D018797:Cell Cycle Proteins; D011506:Proteins; D011994:Recombinant Proteins; C493181:VASH1 protein, human; D042442:Vascular Endothelial Growth Factors