The blind subterranean mole rat superspecies Spalax ehrenbergi has evolved adaptations that allow it to survive and carry out intensive activities in its highly hypoxic underground sealed burrows. A key component of this adaptation is a higher capillary density in some Spalax tissues, primarily in muscles used in digging and in other energetic activities, resulting in a shorter diffusion distance for oxygen. Vascular endothelial growth factor (VEGF) is an angiogenic factor that is critical for angiogenesis during development and is found in response to tissue ischemia. We demonstrate here that due to physiological differences, the Spalax muscle regulatory mechanism for VEGF is different than in Rattus muscle. In vivo, the constitutive level of the VEGF mRNA and the mRNA levels of its transcriptional regulator HIF-1alpha and its mRNA stabilizer HuR are significantly higher in Spalax muscle than in Rattus muscle. Furthermore, as opposed to Rattus, the mRNA levels of HIF-1alpha, HuR, VEGF, as well as that of LDH-A, the enzyme that catalyzes the production of lactate, an accepted marker of anaerobic metabolism, are not increased in Spalax after hypoxia. However, ex vivo, when oxygenation by blood vessels is no longer relevant, the expression pattern of all these genes is similar in the two rodents under both normoxic and hypoxic conditions. Our studies provide evidence that the highly vascularized muscle in Spalax, the most energy consuming tissue during digging, is resistant to the effects of oxygen deprivation. The significance of these results with respect to ischemic vascular disease is abundantly clear.