Repeated thermal therapy up-regulates endothelial nitric oxide synthase and augments angiogenesis in a mouse model of hindlimb ischemia

Circ J. 2006 Apr;70(4):463-70. doi: 10.1253/circj.70.463.


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.

Methods and 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.

Conclusion: Angiogenesis was induced via eNOS using thermal therapy in mice with hindlimb ischemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Blood Pressure
  • Blotting, Western
  • Body Weight
  • Female
  • Heart Rate
  • Hindlimb / blood supply*
  • Hot Temperature / therapeutic use*
  • Ischemia / genetics
  • Ischemia / physiopathology
  • Ischemia / therapy*
  • Laser-Doppler Flowmetry
  • Mice
  • Mice, Inbred Strains
  • NG-Nitroarginine Methyl Ester / pharmacology
  • Neovascularization, Physiologic* / drug effects
  • Nitric Oxide Synthase Type III / genetics*
  • Nitric Oxide Synthase Type III / metabolism
  • Nitrites / blood
  • RNA, Messenger / analysis
  • Temperature
  • Time Factors
  • Up-Regulation


  • Apolipoproteins E
  • Nitrites
  • RNA, Messenger
  • Nitric Oxide Synthase Type III
  • NG-Nitroarginine Methyl Ester