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Acid-Sensing Ion Channels: Novel Mediators of Cerebral Vascular Responses.

RATIONALE
Precise regulation of cerebral blood flow (CBF) is critical for normal brain function. Insufficient CBF contributes to brain dysfunction and neurodegeneration. Carbon dioxide (CO2), via effects on local acidosis, is one of the most potent regulators of CBF. Although a role for nitric oxide (NO) in intermediate signaling has been implicated, mechanisms that initiate CO2 induced-vasodilation remain unclear.


OBJECTIVE
Acid-sensing ion channel-1A (ASIC1A) is a proton-gated cation channel that is activated by extracellular acidosis. Based on work which implicated ASIC1A in the amygdala and bed nucleus of the stria terminalis in CO2-evoked and acid-evoked behaviors, we hypothesized that ASIC1A might also mediate microvascular responses to CO2.


METHODS AND RESULTS
To test this hypothesis we genetically and pharmacologically manipulated ASIC1A and assessed effects on CO2-induced dilation of cerebral arterioles in vivo. Effects of inhalation of 5 or 10% CO2 on arteriolar diameter were greatly attenuated in mice with global deficiency in ASIC1A (Asic1a-/-) or by local treatment with the ASIC inhibitor, psalmotoxin. Vasodilator effects of acetylcholine, which acts via endothelial NO synthase were unaffected, suggesting a non-vascular source of NO may be key for CO2 responses. Thus, we tested whether neurons may be the cell type through which ASIC1A influences microvessels. Using mice in which Asic1a was specifically disrupted in neurons, we found effects of CO2 on arteriolar diameter were also attenuated.


CONCLUSIONS
Together, these data are consistent with a model wherein activation of ASIC1A, particularly in neurons, is critical for CO2CO2-induced NO production and vasodilation. With these findings, ASIC1A emerges as major regulator of microvascular tone.