Endothelin Receptors, Mitochondria and Neurogenesis in Cerebral Ischemia

Background: Neurogenesis is most active during pre-natal development, however, it persists throughout the human lifespan. The putative role of mitochondria in neurogenesis and angiogenesis is gaining importance. Since, ET(B) receptor mediated neurogenesis and angiogenesis has been identified, the role of these receptors with relevance to mitochondrial functions is of interest. Methods: In addition to work from our laboratory, we undertook an extensive search of bibliographic databases for peer-reviewed research literature. Specific technical terms such as endothelin, mitochondria and neurogenesis were used to seek out and critically evaluate literature that was relevant. Results: The ET family consists of three isopeptides (ET-1, ET-2 and ET-3) that produce biological actions by acting on two types of receptors (ET(A) and ET(B)). In the central nervous system (CNS) ET(A) receptors are potent constrictors of the cerebral vasculature and appear to contribute in the causation of cerebral ischemia. ET(A) receptor antagonists have been found to be effective in animal model of cerebral ischemia; however, clinical studies have shown no efficacy. Mitochondrial functions are critically important for several neural development processes such as neurogenesis, axonal and dendritic growth, and synaptic formation. ET appears to impair mitochondrial functions through activation of ET(A) receptors. On the other hand, blocking ET(B) receptors has been shown to trigger apoptotic processes by activating intrinsic mitochondrial pathway. Mitochondria are important for their role in molecular regulation of neurogenesis and angiogenesis. Stimulation of ET(B) receptors in the adult ischemic brain has been found to promote angiogenesis and neurogenesis mediated through vascular endothelial growth factor and nerve growth factor. It will be interesting to investigate the effect of ET(B) receptor stimulation on mitochondrial functions in the CNS following cerebral ischemia. Conclusion: The findings of this review implicate brain ET(B) receptors in angiogenesis and neurogenesis following cerebral ischemia, it is possible that the positive effect of stimulating ET(B) receptors in cerebral ischemia may be mediated through mitochondrial functions.