Distinctive localization and opposed roles of vasohibin-1 and vasohibin-2 in the regulation of angiogenesis.
We recently isolated a novel angiogenesis inhibitor, vasohibin-1, and its homologue, vasohibin-2. In this study we characterize the role of these 2 molecules in the regulation of angiogenesis. In a mouse model of subcutaneous angiogenesis, the expression of endogenous vasohibin-1 was low in proliferating ECs at the sprouting front but high in nonproliferating endothelial cells (ECs) in the termination zone. In contrast, endogenous vasohibin-2 was preferentially expressed in mononuclear cells mobilized from bone marrow that infiltrated the sprouting front. When applied exogenously, vasohibin-1 inhibited angiogenesis at the sprouting front where endogenous vasohibin-1 was scarce but did not influence vascularity in the termination zone where endogenous vasohibin-1 was enriched. Exogenous vasohibin-2 prevented the termination of angiogenesis in the termination zone and increased vascularity in this region. Angiogenesis was persistent in the termination zone in the vasohibin-1 knockout mice, whereas angiogenesis was deficient at the sprouting front in the vasohibin-2 knockout mice. Supplementation of deficient proteins normalized the abnormal patterns of angiogenesis in the vasohibin knockout mice. These results indicate that vasohibin-1 is expressed in ECs in the termination zone to halt angiogenesis, whereas vasohibin-2 is expressed in infiltrating mononuclear cells in the sprouting front to promote angiogenesis.
Kimura
Hiroshi
H
Department of Vascular Biology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan
Miyashita
Hiroki
H
Suzuki
Yasuhiro
Y
Kobayashi
Miho
M
Watanabe
Kazuhide
K
Sonoda
Hikaru
H
Ohta
Hideki
H
Fujiwara
Takashi
T
Shimosegawa
Tooru
T
Sato
Yasufumi
Y
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007124:Immunoenzyme Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic; D018919:Neovascularization, Physiologic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism
D018797:Cell Cycle Proteins; D012333:RNA, Messenger; C493181:VASH1 protein, human; C510089:Vash1 protein, mouse