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Ventromedial Hypothalamus Activation Aggravates Hypertension Myocardial Remodeling Through the Sympathetic Nervous System

ABSTRACT: Background: The ventromedial hypothalamus (VMH) is an important nuclei in responding to emotional stress, and emotional stress is a risk factor for cardiovascular diseases. However, the role of the VMH in cardiovascular diseases remains unknown. This study aimed to investigate the effects and underlying mechanisms of VMH activation on hypertension related cardiac remodeling in two-kidney-one-clip (2K1C) hypertension (HTN) rats. Methods: Eighteen male Sprague-Dawley rats were injected with AAV-hSyn-hM3D(Gq) into the VMH at 0 weeks and then randomly divided into three groups: (1) sham group (sham 2K1C + saline i.p. injection); (2) HTN group (2K1C + saline i.p. injection); (3) HTN+VMH activation group (2K1C + clozapine-N-oxide i.p. injection). One week later, rats were subjected to a sham or 2K1C operation, and 2 weeks later rats were injected with clozapine-N-oxide or saline for 2 weeks. Results: In the HTN+VMH activation group, FosB expression was significantly increased in VMH sections compared with those of the other two groups. Compared to the HTN group, the HTN+VMH activation group showed significant: (1) increases in systolic blood pressure (SBP); (2) exacerbation of cardiac remodeling; and (3) increases in serum norepinephrine levels and sympathetic indices of heart rate variability. Additionally, myocardial RNA-sequencing analysis showed that VMH activation might regulate the HIF-1 and PPAR signal pathway and fatty acid metabolism. qPCR results confirmed that the relative mRNA expression of HIF-1α was increased and the PPARα and CPT-1 mRNA expression were decreased in the HTN+VMH activation group compared to the HTN group. Conclusions: VMH activation could increase SBP and aggravate cardiac remodeling possibly by sympathetic nerve activation and the HIF-1α/PPARα/CPT-1 signaling pathway might be the underlying mechanism.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC8558385 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsThe carotid bodies (CBs) of spontaneously hypertensive (SH) rats exhibit hypertonicity and hyperreflexia contributing to heightened peripheral sympathetic outflow. We hypothesized that CB hyperexcitability is driven by its own sympathetic innervation.Methods and resultsTo test this, the chemoreflex was activated (NaCN 50-100 µL, 0.4 µg/µL) in SH and Wistar rats in situ before and after: (i) electrical stimulation (ES; 30 Hz, 2 ms, 10 V) of the superior cervical ganglion (SCG), which innervates the CB; (ii) unilateral resection of the SCG (SCGx); (iii) CB injections of an α1-adrenergic receptor agonist (phenylephrine, 50 µL, 1 mmol/L), and (iv) α1-adrenergic receptor antagonist prazosin (40 µL, 1 mmol/L) or tamsulosin (50 µL, 1 mmol/L). ES of the SCG enhanced CB-evoked sympathoexcitation by 40-50% (P < 0.05) with no difference between rat strains. Unilateral SCGx attenuated the CB-evoked sympathoexcitation in SH (62%; P < 0.01) but was without effect in Wistar rats; it also abolished the ongoing firing of chemoreceptive petrosal neurones of SH rats, which became hyperpolarized. In Wistar rats, CB injections of phenylephrine enhanced CB-evoked sympathoexcitation (33%; P < 0.05), which was prevented by prazosin (26%; P < 0.05) in SH rats. Tamsulosin alone reproduced the effects of prazosin in SH rats and prevented the sensitizing effect of the SCG following ES. Within the CB, α1A- and α1B-adrenoreceptors were co-localized on both glomus cells and blood vessels. In conscious SH rats instrumented for recording blood pressure (BP), the CB-evoked pressor response was attenuated after SCGx, and systolic BP fell by 16 ± 4.85 mmHg.ConclusionsThe sympathetic innervation of the CB is tonically activated and sensitizes the CB of SH but not Wistar rats. Furthermore, sensitization of CB-evoked reflex sympathoexcitation appears to be mediated by α1-adrenoceptors located either on the vasculature and/or glomus cells. The SCG is novel target for controlling CB pathophysiology in hypertension.

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Ventromedial Hypothalamus Activation Aggravates Hypertension Myocardial Remodeling Through the Sympathetic Nervous System

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