Repeated thermal therapy up-regulates endothelial nitric oxide synthase and augments angiogenesis in a mouse model of hindlimb ischemia.
BACKGROUND
Nitric oxide (NO), constitutively produced by endothelial NO synthase (eNOS), plays roles in angiogenesis. Having reported that thermal therapy up-regulated the expression of arterial eNOS in hamsters, we investigated whether this therapy increased angiogenesis in mice with hindlimb ischemia.


RESULTS
Unilateral hindlimb ischemia was induced in apolipoprotein E-deficient mice, which were divided into control and thermal therapy groups. The latter mice were placed in a far-infrared dry sauna at 41 degrees C for 15 min and then at 34 degrees C for 20 min once daily for 5 weeks. Laser Doppler perfusion imaging demonstrated that the ischemic limb/normal side blood perfusion ratio in the thermal therapy group was significantly increased beyond that in controls (0.79+/-0.04 vs 0.54+/-0.08, p<0.001). Significantly greater capillary density was seen in thermal therapy group (757+/-123 /mm2 vs 416+/-20 /mm2, p<0.01). Western blotting showed thermal therapy markedly increased hindlimb eNOS expression. To study possible involvement of eNOS in thermally induced angiogenesis, thermal therapy was given to mice with hindlimb ischemia with or without N(G)-nitro-L-arginine methyl ester (L-NAME) administration for 5 weeks. L-NAME treatment eliminated angiogenesis induced using thermal therapy. Thermal therapy did not increase angiogenesis in eNOS-deficient mice.


CONCLUSIONS
Angiogenesis was induced via eNOS using thermal therapy in mice with hindlimb ischemia.
Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, Sakuragaoka, Japan.
Yuichi
Y
Akasaki
Masaaki
M
Miyata
Hideyuki
H
Eto
Takahiro
T
Shirasawa
Narisato
N
Hamada
Yoshiyuki
Y
Ikeda
Sadatoshi
S
Biro
Yutaka
Y
Otsuji
Chuwa
C
Tei
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D001794:Blood Pressure; D015153:Blotting, Western; D001835:Body Weight; D005260:Female; D006339:Heart Rate; D006614:Hindlimb / Q000098:blood supply*; D006358:Hot Temperature / Q000627:therapeutic use*; D007511:Ischemia / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D017078:Laser-Doppler Flowmetry; D051379:Mice; D008815:Mice, Inbred Strains; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000235:genetics* / Q000378:metabolism; D009573:Nitrites / Q000097:blood; D012333:RNA, Messenger / Q000032:analysis; D013696:Temperature; D013997:Time Factors; D015854:Up-Regulation
D001057:Apolipoproteins E; D009573:Nitrites; D012333:RNA, Messenger; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester