Important role of apoptosis signal-regulating kinase 1 in ischemia-induced angiogenesis.
OBJECTIVE
We first examined the role of apoptosis signal-regulating kinase 1 (ASK1), one of mitogen-activated protein kinase kinase kinases, in ischemia-induced angiogenesis.


RESULTS
Unilateral hindlimb ischemia was induced surgically in C57BL/6J wild-type (WT) mice or mice deficient in ASK1 (ASK1(-/-)). ASK1 activity in WT mouse hindlimb was increased dramatically after ischemia. By laser Doppler analysis, well-developed collateral vessels and angiogenesis were observed in WT mice in response to hindlimb ischemia, whereas these responses were reduced in ASK1(-/-) mice. Immunostaining revealed that infiltration of macrophages and T lymphocytes was suppressed in the ischemic tissues of ASK1(-/-) mice compared with WT mice. The expression of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein-1 (MCP-1) proteins in ischemic tissues was weaker in ASK1(-/-) mice compared with WT mice. In vitro study on endothelial cells indicated that dominant-negative ASK1 significantly attenuated hydrogen peroxide-induced VEGF and MCP-1 production. Furthermore, in vivo blockade of MCP-1 by its neutralizing antibody suppressed the recovery of the blood flow and capillary formation after ischemia.


CONCLUSIONS
ASK1 pathway promotes early angiogenesis by inducing inflammatory cell infiltration and VEGF and MCP-1 expression. ASK1 may provide the basis for the development of new therapeutic strategy for angiogenesis.
Department of Pharmacology, Osaka City University Medical School, Japan.
Yasukatsu
Y
Izumi
Shokei
S
Kim-Mitsuyama
Minoru
M
Yoshiyama
Takashi
T
Omura
Masayuki
M
Shiota
Atsushi
A
Matsuzawa
Tokihito
T
Yukimura
Toyoaki
T
Murohara
Motohiro
M
Takeya
Hidenori
H
Ichijo
Junichi
J
Yoshikawa
Hiroshi
H
Iwao
D000818:Animals; D002196:Capillaries / Q000502:physiology; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007511:Ischemia / Q000276:immunology* / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D014471:Umbilical Veins / Q000166:cytology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D042461:Vascular Endothelial Growth Factor A; D020928:Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse