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

Jan Wenzel, Cathrin E. Hansen, Carla Bettoni, Miriam A. Vogt, Beate Lembrich, Rentsenkhand Natsagdorj, Gianna Huber, Josefine Brands, Kjestine Schmidt, Julian C. Assmann, Ines Stölting, Kathrin Saar, Jan Sedlacik, Jens Fiehler, Peter Ludewig, Michael Wegmann, Nina Feller, Marius Richter, Helge Müller-Fielitz, Thomas WaltherGabriele M. König, Evi Kostenis, Walter Raasch, Norbert Hübner, Peter Gass, Stefan Offermanns, Cor De Wit, Carsten A. Wagner, Markus Schwaninger*

*Corresponding author for this work
4 Citations (Scopus)


Carbon dioxide (CO2), 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 Gαq/11 proteins mediate the CO2/H+ effect on cerebrovascular reactivity in mice. CO2/H+ leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO2, if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO2 dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO2 effect on anxiety. Even at atmospheric CO2 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 CO2 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.

Original languageEnglish
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number3
Pages (from-to)1753-1761
Number of pages9
Publication statusPublished - 21.01.2020

Research Areas and Centers

  • Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)

DFG Research Classification Scheme

  • 205-17 Endocrinology, Diabetology, Metabolism


Dive into the research topics of 'Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice'. Together they form a unique fingerprint.

Cite this