Abstract
Objective Stress-induced hypertension (SIH) is driven by sympathetic overactivity, with the rostral ventrolateral medulla (RVLM) serving as a key regulatory hub. Extracellular vesicles (EVs) mediate intercellular communication, but their role in RVLM-related SIH pathogenesis remains unclear.Methods A rat SIH model was established via 15 days of unpredictable stress. The EV secretion inhibitor GW4869 was microinjected into the RVLM of SIH rats to observe alterations in blood pressure and neuronal excitability. RVLM-EVs were isolated using iodixanol density gradient centrifugation and used to treat primary RVLM neurons in vitro; neuronal excitability was evaluated by c-FOS immunofluorescence staining. Bead-based flow cytometry was performed to detect the protein components of RVLM-EVs, and the TNF-α antagonist R7050 was administered for both in vitro and in vivo interventions to examine its regulatory effects on neuronal excitability and blood pressure.Results GW4869 reduced BP and neuronal excitability in SIH rats. SIH-RVLM-EVs, with larger particle size, were internalized by primary RVLM neurons, enhancing excitability and inducing hypertension in normotensive rats. TNF-α was enriched in SIH-RVLM-EVs; R7050 abrogated these pro-hypertensive effects in vitro and in vivo.Conclusion RVLM-derived EVs promote SIH by delivering TNF-α, which enhances RVLM pre-sympathetic neuronal excitability and sympathetic overactivity. TNF-α in RVLM-EVs is a promising therapeutic target for SIH.