Single-nucleus RNA sequencing reveals Cntnap2+ astrocytes triggering a hypertensive effect in the rostral ventrolateral medulla by disrupting glutamate uptake

作者：Shuai Zhang, Lei Tong, Zhangyan Ren, Tengteng Dai, Linping Wang, Dongfei Zhu, Haisheng Liu, Liucun Zhu, Dong Huang, Dongshu Du · 发表于：Journal of Advanced Research · 年份：2025 · DOI：10.1016/j.jare.2025.06.002 · 被引用次数：3 · 研究领域：Neuroscience of respiration and sleep、Renin-Angiotensin System Studies、Congenital heart defects research

INTRODUCTION: The rostral ventrolateral medulla (RVLM) is a vital vasomotor nucleus involved in hypertension control. However, the molecular intricacies within RVLM cells, particularly in non-neuronal cell populations such as astrocytes, under hypertensive conditions remain to be systematically investigated. OBJECTIVES: We aimed to elucidate cellular heterogeneity in the RVLM at single-cell resolution, with a focus on astrocytes, to further characterize its role in hypertension. METHODS: Transcriptional changes in cells in the RVLM after hypertension were examined by using single-nucleus RNA sequencing (snRNA-seq). Further experiments, like radiotelemetry and immunofluorescence assays, were conducted to support the findings of snRNA-seq. RESULTS: . The expression of Cntnap2 in RVLM astrocytes was notably increased to approximately 2.0-fold (P < 0.001) upon hypertension. Astrocyte-specific Cntnap2 overexpression in RVLM of WKY rats significantly enhanced neuronal excitability (∼21.5-fold, P < 0.001), sympathetic outflow (∼4.2-fold, P < 0.001), and blood pressure (BP, ∼1.5-fold, P < 0.001). Astrocyte-specific Cntnap2 knockdown in RVLM of SHRs resulted in 71 % reduction in neuronal excitability (P < 0.001), 51.6 % decrease in sympathetic outflow (P < 0.01), and 12.6 % drop in BP (P < 0.01). Elevated levels of Cntnap2 in primary astrocytes markedly increased primary neuron excitability to approximately 8.2-fold (P < 0.001). Mechanistically, Cntnap2 upregulation decreased Eaat2 ex...