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Post-exercise hypotension (PEH) is an immediate reduction in blood pressure (BP) after a single bout of exercise that forms the long-term hypertension amelioration by chronic exercise. The present study aims to explore a novel mechanism of PEH, with a focus of skeletal muscle-derived extracellular vesicles (SkM-EVs). We hypothesize that repetitively contracting-relaxing muscle releases antioxidant-enriched EVs that induce hypotension. Experiments were carried out in 48 male Sprague-Dawley rats. BP was recorded by a Millar catheter inserted into right carotid artery. EVs were isolated from SkM and plasma using ultracentrifugation, and then qualified and quantified using transmission electron microscopy and the ZetaView nanoparticle tracking analyzer. Results: First, in rats undergoing 1-hour of treadmill exercise (15/30/15 m/min for 10/40/10 min), we found an elevated BP during exercise (34.7 ± 5.2 mmHg, p < 0.001; n = 8), followed by a decrease in BP below baseline during the post exercise period (-7.3 ± 1.1 mmHg, p < 0.01). Pretreatment with the EV inhibitor GW4869 (1.5 mg/kg) had no effects on hypertension during exercise, but completely abolished the post-exercise hypotension (1.93 ± 0.64 mmHg, p < 0.001), suggesting a role for SkM-EVs in this response. Bolus i.v. injection of SkM-EVs from exercised rats (400 μg EV protein) induced a dramatic decrease in BP (-16.7 ± 4.4 mmHg; p < 0.01, n = 6/group) in non-exercised rats, which lasted for up to 40 min. Second, 1-hour sciatic nerve electrical stimulation (2.5V, 50Hz, 0.3s/3s)-evoked hindlimb muscle contraction in isoflurane-anesthetized rats induced a biphasic change in BP, with hypertension during the initial 20 min followed by hypotension in the last 40 min. Transection of the sciatic nerve or pretreatment with GW4869 abolished the stimulation-evoked hypertension and hypotension. Bolus i.v. injection of EVs from contracting-muscle significantly reduced BP with a maximal change of -14 ± 3.2 mmHg (p = 0.003; n = 5). Third, mass spectroscopic and western blotting analyses of these EVs identified 827 proteins, including Catalase, GSTMs, PRDXs, EPHX1, HSP90, and many others, which are involved in redox homeostasis and mitochondrial bioenergetics. Finally, using muscle-specific GFP reporter mice (MS-mG), we found increased SkM-EVs in both muscle and plasma following exercise by using flow cytometry. Confocal imaging identified GFP+-particles in the neurons of the rostral ventrolateral medulla (RVLM) of C57BL/6 mice that received an injection of SkM-EVs isolated from the exercised MS-mG mice, suggesting their active uptake across the blood-brain barrier. In summary, the major findings of this study include (1) SkM-EVs are essential for PEH; (2) i.v. administration of SkM-EVs reduced BP; (3) SkM-EVs contain enriched antioxidant enzymes and other cytoprotective proteins. These results suggest a novel mechanism underpinning PEH and provides a potential therapeutic strategy for hypertension. Supported by NIH grant R01HL160820. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.