Tissue responses to ischemia: local and remote responses for preserving perfusion of ischemic muscle.

Abstract

The sequence of biological events that permits an organism to maintain tissue viability in the face of acute or chronic ischemia constitutes a fundamental survival response. Among mammalian species, this response may be best exemplified by the Israeli mole-rat (1), a creature that lives only in Egypt, Israel, and Syria. What is fascinating about this animal is that its entire life is spent underground in subterranean burrows at decidedly low oxygen tensions; accordingly, its tissues have been shown to be highly vascularized, and the vascular density is associated with upregulated endogenous expression of VEGF. Among supraterranean species confronted with tissue ischemia localized to cardiac or skeletal muscle, at least two options are available. The first is to reduce demand for tissue oxygenation. This may be accomplished by “biochemical splinting,” in which metabolic functions are converted from primarily aerobic to predominantly anaerobic. In the extreme, reduced blood flow may be associated with literal splinting, that is impaired wall motion characteristic of hibernating myocardium (2). Alternatively, “behavioral splinting” may be employed. For cardiac muscle, this may be achieved by reduced activity and, if necessary, pharmacologic therapies that reduce myocardial wall stress. For skeletal muscle, pharmacologic interventions are so limited that reduced levels of activity constitute the typical response to claudication. These adjustments, however, are necessary only if natural reparative mechanisms have failed to address the problem of ischemia successfully by restoring blood flow to the affected muscle group. Our current notions concerning the means by which this is achieved, as well as the factors that may selectively obviate this adaptive response, are the subject of this Perspective.