Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivo
Alison Xiaoqiao Xie, Jakovin J. Lee, Ken D. McCarthy
Alison Xiaoqiao Xie, Jakovin J. Lee, Ken D. McCarthy
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Research Article Cardiology Neuroscience

Ganglionic GFAP+ glial Gq-GPCR signaling enhances heart functions in vivo

Abstract

The sympathetic nervous system (SNS) accelerates heart rate, increases cardiac contractility, and constricts resistance vessels. The activity of SNS efferent nerves is generated by a complex neural network containing neurons and glia. Gq G protein–coupled receptor (Gq-GPCR) signaling in glial fibrillary acidic protein–expressing (GFAP+) glia in the central nervous system supports neuronal function and regulates neuronal activity. It is unclear how Gq-GPCR signaling in GFAP+ glia affects the activity of sympathetic neurons or contributes to SNS-regulated cardiovascular functions. In this study, we investigated whether Gq-GPCR activation in GFAP+ glia modulates the regulatory effect of the SNS on the heart; transgenic mice expressing Gq-coupled DREADD (designer receptors exclusively activated by designer drugs) (hM3Dq) selectively in GFAP+ glia were used to address this question in vivo. We found that acute Gq-GPCR activation in peripheral GFAP+ glia significantly accelerated heart rate and increased left ventricle contraction. Pharmacological experiments suggest that the glial-induced cardiac changes were due to Gq-GPCR activation in satellite glial cells within the sympathetic ganglion; this activation led to increased norepinephrine (NE) release and beta-1 adrenergic receptor activation within the heart. Chronic glial Gq-GPCR activation led to hypotension in female Gfap-hM3Dq mice. This study provides direct evidence that Gq-GPCR activation in peripheral GFAP+ glia regulates cardiovascular functions in vivo.

Authors

Alison Xiaoqiao Xie, Jakovin J. Lee, Ken D. McCarthy

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Figure 6

Chronic glial activation leads to hypotension and left ventricle dilation in female Gfap-hM3Dq mice.

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Chronic glial activation leads to hypotension and left ventricle dilatio...
Littermate controls, n = 9; Gfap-hM3Dq, n = 10 throughout the figure. (A) Schematic model for chronic activation of ganglionic SGCs and potential cardiovascular outcomes. (B) Chronic CNO treatment experiment timeline. (C) Chronic CNO-induced glial activation led to a significant decrease in body weight in female Gfap-hM3Dq mice but not female littermate controls at the end of the treatment period (2-way ANOVA, ***P < 0.0001, time and genotype interaction). (D) Chronic CNO-induced glial activation led to hypotension in female Gfap-h3Dq animals relative to littermate controls (Mann-Whitney U test, **P < 0.01, ***P < 0.001). (E) Echocardiogram recordings showed that chronic CNO treatment led to increased left ventricle diameter at the end of the diastolic cycle (left ventricular internal diameter end diastole [LVID;d]) in female Gfap-hM3Dq mice compared with female littermate controls (Mann-Whitney U test, P < 0.05). IVS;d and IVS;s, interventricular septal end diastole and end systole. LVPW;d and LVPW;s, left ventricular posterior wall end diastole and end systole. (F) The volume of the left ventricle at the end of diastolic cycle was significantly increased in female Gfap-hM3Dq mice after 2 weeks of CNO treatment (Mann-Whitney U test, *P < 0.05). (G and H) Chronic CNO treatment did not result in changes in ejection fraction (G) or fraction shortening (H) in female Gfap-hM3Dq animals compared with littermate controls (Mann-Whitney U test). (I) The weight of the hearts of female Gfap-hM3Dq animals did not change after chronic CNO treatment (Mann-Whitney U test).