Mitochondrial depolarization in endothelial and other vascular cells and their role in the regulation of cerebral vascular tone

Abstract

Mitochondrial initiated events of the diverse cells types comprising the neurovascular unit promote changes in cerebrovascular tone through multiple signaling pathways. Activation of the adenosine triphosphate (ATP)-dependent potassium channels on the inner mitochondrial membrane (mitoKATPchannels) leads to mitochondrial depolarization as well as activation of cell-specifi c signaling mechanisms in endothelium, vascular smooth muscle (VSM), and perivascular and parenchymal nerves resulting in an integrated dilator response of cerebral arteries. Activation of mitoK ATPchannels relaxes VSM via generation of calcium sparks and subsequent downstream signaling mechanisms, and this relaxation can be augmented by nitric oxide (NO) produced by mitoK ATPchannel activation in endothelium and adjacent neurons. Some research suggests that calcium activated potassium channels may also be present in mitochondria (mitoK Cachannels) and may affect cerebral vascular tone, but more research is needed to support this view. Pre-existing chronic conditions such as insulin resistance (IR) and/or diabetes impair mitoK ATPchannel-relaxation of cerebral arteries. Surprisingly, mitoK ATPchannel function after intense stress such as ischemia appears to be retained in large cerebral arteries despite generalized cerebral vascular dysfunction. Production of vasoactive factors following activation of mitochondria in response to physiological stimuli in one or more of the cells comprising the neurovascular unit may represent the elusive signaling link between metabolic rate and blood fl ow. In addition, our data indicate that mitoK ATP channels represent an important, but underutilized target toward improving vascular dysfunction and decreasing brain injury in stroke patients.