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 2

Acute activation of hM3Dq in GFAP+ glia led to robust, beta adrenergic receptor–mediated increases in heart rate and left ventricular contractility in Gfap-hM3Dq mice.

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Acute activation of hM3Dq in GFAP+ glia led to robust, beta adrenergic r...
(A) Schematic of in vivo model: CNO-induced hM3Dq activation in GFAP+ glia leads to changes in SNS-driven cardiovascular functions in Gfap-hM3Dq mice. (B) Heart rate recordings showed that 10 mg/kg (S)-atenolol blocked isoprenaline-induced increases in heart rate in C56BL/6J mice in vivo (6 recordings/2 mice). (C) CNO-induced significant increases in heart rate in Gfap-hM3Dq mice over 15 minutes compared with littermate controls (n = 5–7 mice in each group; 2-way ANOVA, ***P < 0.0001, time and genotype interaction between Gfap-hM3Dq and littermate controls), which were blocked by (S)-atenolol in vivo (2-way ANOVA, ###P < 0.0001, time and treatment interaction between two Gfap-hM3Dq groups). Saline or atenolol were injected 10 minutes before CNO. (D) CNO-induced increases in left ventricle functions 15 minutes after CNO injections. Saline or atenolol was injected 10 minutes before CNO. (E) Significant increases in ejection fraction (EF) and (F) fraction shortening (FS) after CNO administration in Gfap-hM3Dq mice (unpaired t test; **P < 0.01 between littermate control and Gfap-hM3Dq mice, also between two Gfap-hM3Dq groups; n = 10 for each genotype), which were blocked by (S)-atenolol pretreatment (unpaired t test; ****P < 0.00001 between the two Gfap-hM3Dq groups; n = 10 for each genotype). (G) Schematic model for potential mechanisms (red lines) underlying CNO-induced cardiac changes in vivo in Gfap-hM3Dq mice. nAChR, nicotinic acetylcholine receptors; SPGN, spinal preganglionic neurons.