Vascular control of the CO₂/H⁺-dependent drive to breathe

Respiratory chemoreceptors regulate breathing in response to changes in tissue CO₂/H⁺. Blood flow is a fundamental determinant of tissue CO₂/H⁺, yet little is known regarding how regulation of vascular tone in chemoreceptor regions contributes to respiratory behavior. Previously, we showed in rat that CO₂/H⁺-vasoconstriction in the retrotrapezoid nucleus (RTN) supports chemoreception by a purinergic-dependent mechanism (Hawkins et al., 2017). Here, we show in mice that CO₂/H⁺ dilates arterioles in other chemoreceptor regions, thus demonstrating CO₂/H⁺ vascular reactivity in the RTN is unique. We also identify P2Y₂ receptors in RTN smooth muscle cells as the substrate responsible for this response. Specifically, pharmacological blockade or genetic deletion of P2Y₂ from smooth muscle cells blunted the ventilatory response to CO₂, and re-expression of P2Y₂ receptors only in RTN smooth muscle cells fully rescued the CO₂/H⁺ chemoreflex. These results identify P2Y₂ receptors in RTN smooth muscle cells as requisite determinants of respiratory chemoreception.