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


Wenzel, Jan; Hansen, Cathrin E; Bettoni, Carla; et al (2020). Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice. Proceedings of the National Academy of Sciences of the United States of America, 117(3):1753-1761.

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.

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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Scopus Subject Areas:Health Sciences > Multidisciplinary
Language:English
Date:21 January 2020
Deposited On:29 Jan 2020 13:31
Last Modified:01 Aug 2020 18:02
Publisher:National Academy of Sciences
ISSN:0027-8424
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1073/pnas.1907467117
PubMed ID:31896584

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