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.
Taniguchi
Koji
K
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Sasaki
Ken-ichiro
K
Watari
Kousuke
K
Yasukawa
Hideo
H
Imaizumi
Tsutomu
T
Ayada
Toranoshin
T
Okamoto
Fuyuki
F
Ishizaki
Takuma
T
Kato
Reiko
R
Kohno
Ri-ichiro
R
Kimura
Hiroshi
H
Sato
Yasufumi
Y
Ono
Mayumi
M
Yonemitsu
Yoshikazu
Y
Yoshimura
Akihiko
A
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