Suppression of Sproutys has a therapeutic effect for a mouse model of ischemia by enhancing angiogenesis.
Sprouty proteins (Sproutys) inhibit receptor tyrosine kinase signaling and control various aspects of branching morphogenesis. In this study, we examined the physiological function of Sproutys in angiogenesis, using gene targeting and short-hairpin RNA (shRNA) knockdown strategies. Sprouty2 and Sprouty4 double knockout (KO) (DKO) mice were embryonic-lethal around E12.5 due to cardiovascular defects. The number of peripheral blood vessels, but not that of lymphatic vessels, was increased in Sprouty4 KO mice compared with wild-type (WT) mice. Sprouty4 KO mice were more resistant to hind limb ischemia and soft tissue ischemia than WT mice were, because Sprouty4 deficiency causes accelerated neovascularization. Moreover, suppression of Sprouty2 and Sprouty4 expression in vivo by shRNA targeting accelerated angiogenesis and has a therapeutic effect in a mouse model of hind limb ischemia. These data suggest that Sproutys are physiologically important negative regulators of angiogenesis in vivo and novel therapeutic targets for treating peripheral ischemic diseases.
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Koji
K
Taniguchi
Ken-ichiro
K
Sasaki
Kousuke
K
Watari
Hideo
H
Yasukawa
Tsutomu
T
Imaizumi
Toranoshin
T
Ayada
Fuyuki
F
Okamoto
Takuma
T
Ishizaki
Reiko
R
Kato
Ri-ichiro
R
Kohno
Hiroshi
H
Kimura
Yasufumi
Y
Sato
Mayumi
M
Ono
Yoshikazu
Y
Yonemitsu
Akihiko
A
Yoshimura
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001808:Blood Vessels / Q000473:pathology; D003315:Cornea / Q000098:blood supply; D004195:Disease Models, Animal; D006614:Hindlimb / Q000098:blood supply; D047908:Intracellular Signaling Peptides and Proteins; D007511:Ischemia / Q000503:physiopathology* / Q000628:therapy*; D042601:Lymphatic Vessels / Q000473:pathology; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; C499037:Spry4 protein, mouse; D017346:Protein Serine-Threonine Kinases; C118389:Spry2 protein, mouse