Vascular control of the CO(2)/H(+)-dependent drive to breathe

Respiratory chemoreceptors regulate breathing in response to changes in tissue CO(2)/H(+). Blood flow is a fundamental determinant of tissue CO(2)/H(+), yet little is known regarding how regulation of vascular tone in chemoreceptor regions contributes to respiratory behavior. Previously, we showed in rat that CO(2)/H(+)-vasoconstriction in the retrotrapezoid nucleus (RTN) supports chemoreception by a purinergic-dependent mechanism (Hawkins et al., 2017). Here, we show in mice that CO(2)/H(+) dilates arterioles in other chemoreceptor regions, thus demonstrating CO(2)/H(+) vascular reactivity in the RTN is unique. We also identify P2Y(2) receptors in RTN smooth muscle cells as the substrate responsible for this response. Specifically, pharmacological blockade or genetic deletion of P2Y(2) from smooth muscle cells blunted the ventilatory response to CO(2), and re-expression of P2Y(2) receptors only in RTN smooth muscle cells fully rescued the CO(2)/H(+) chemoreflex. These results identify P2Y(2) receptors in RTN smooth muscle cells as requisite determinants of respiratory chemoreception.