Impaired Endothelium-Mediated Cerebrovascular Reactivity Promotes Anxiety and Respiration Disorders in Mice
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Impaired Endothelium-Mediated Cerebrovascular Reactivity Promotes Anxiety and Respiration Disorders in Mice. / Wenzel, Jan; Hansen, Cathrin E; Bettoni, Carla; Vogt, Miriam A; Lembrich, Beate; Natsagdorj, Rentsenkhand; Huber, Gianna; Brands, Josefine; Schmidt, Kjestine; Assmann, Julian C; Stölting, Ines; Saar, Kathrin; Sedlacik, Jan; Fiehler, Jens; Ludewig, Peter; Wegmann, Michael; Feller, Nina; Richter, Marius; Müller-Fielitz, Helge; Walther, Thomas; König, Gabriele M; Kostenis, Evi; Raasch, Walter; Hübner, Norbert; Gass, Peter; Offermanns, Stefan; de Wit, Cor; Wagner, Carsten A; Schwaninger, Markus.
In: P NATL ACAD SCI USA, Vol. 117, No. 3, 21.01.2020, p. 1753-1761.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Impaired Endothelium-Mediated Cerebrovascular Reactivity Promotes Anxiety and Respiration Disorders in Mice
AU - Wenzel, Jan
AU - Hansen, Cathrin E
AU - Bettoni, Carla
AU - Vogt, Miriam A
AU - Lembrich, Beate
AU - Natsagdorj, Rentsenkhand
AU - Huber, Gianna
AU - Brands, Josefine
AU - Schmidt, Kjestine
AU - Assmann, Julian C
AU - Stölting, Ines
AU - Saar, Kathrin
AU - Sedlacik, Jan
AU - Fiehler, Jens
AU - Ludewig, Peter
AU - Wegmann, Michael
AU - Feller, Nina
AU - Richter, Marius
AU - Müller-Fielitz, Helge
AU - Walther, Thomas
AU - König, Gabriele M
AU - Kostenis, Evi
AU - Raasch, Walter
AU - Hübner, Norbert
AU - Gass, Peter
AU - Offermanns, Stefan
AU - de Wit, Cor
AU - Wagner, Carsten A
AU - Schwaninger, Markus
PY - 2020/1/21
Y1 - 2020/1/21
N2 - 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.
AB - 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.
KW - Amygdala
KW - Animals
KW - Anxiety/metabolism
KW - Arterioles/pathology
KW - Brain/physiology
KW - Brain Stem/metabolism
KW - Carbon Dioxide/metabolism
KW - Cardiovascular System/metabolism
KW - Central Nervous System/metabolism
KW - Disease Models, Animal
KW - Endothelium/metabolism
KW - GTP-Binding Protein alpha Subunits, Gq-G11/genetics
KW - Gene Expression
KW - Humans
KW - Hypercapnia/metabolism
KW - Mice
KW - Mice, Knockout
KW - Mice, Transgenic
KW - Receptors, G-Protein-Coupled/genetics
KW - Respiration
KW - Respiration Disorders/metabolism
KW - Risk Factors
KW - Signal Transduction
U2 - https://doi.org/10.1073/pnas.1907467117
DO - https://doi.org/10.1073/pnas.1907467117
M3 - SCORING: Journal article
C2 - 31896584
VL - 117
SP - 1753
EP - 1761
JO - P NATL ACAD SCI USA
JF - P NATL ACAD SCI USA
SN - 0027-8424
IS - 3
ER -