Normoxic low-altitude simulation (at 714 mmHg) improves limb blood perfusion in mice with hindlimb ischemia

Humans have fewer cardiovascular events and improved outcomes after cardiovascular events when living at low and moderate altitudes (<3000 m) above sea level. We have previously shown that low-altitude simulation using reductions in barometric pressure enhances vasodilation ex vivo in arterial segments and reduces systemic vascular resistance in vivo and can also improve left ventricular function after a myocardial infarction. We hypothesize that low-altitude simulation could also improve hindlimb ischemia, a model of peripheral artery disease in humans. We performed femoral artery ligation to generate hindlimb ischemia in 3-month-old C57BL6 mice. Control group mice (n = 10) recovered at 754 mmHg (control) for 14 days. Treatment group mice (n = 15) were placed in a low-altitude simulation chamber (at 714 mmHg) to recover from surgery for 3-hours daily for 14 days. Hindlimb perfusion imaging using a laser Doppler line scanner was performed for all mice prior to the surgery, and then on days 1, 3, 7, and 14 post-surgery. At 2 weeks, ischemic reserve was significantly higher in the treatment group mice (0.50 ± 0.13 vs. 0.20 ± 0.06; p = 0.01). Treatment mice had higher functional scores and were able to walk better at two weeks. There was approximately three times less HIF1α found via western blotting and a small but statistically significant improvement of lectin perfusion in calf tissue of treatment mice. We conclude that low-altitude simulation improves blood perfusion in murine hindlimb ischemia. This approach may have therapeutic implications for humans with peripheral artery disease.