Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice

Abstract

Carbon dioxide (CO 2 ), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H + receptor, and endothelial Gα q/11 proteins mediate the CO 2 /H + effect on cerebrovascular reactivity in mice. CO 2 /H + leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO 2 , if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO 2 dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO 2 effect on anxiety. Even at atmospheric CO 2 concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function. The site-specific reactivity of vessels to CO 2 is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells. Our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.