Excessive sympathetic activity and
norepinephrine (NE) release play crucial roles in the pathogeneses of
hypertension. Sympathetic fibers innervate adventitia rather than media of arteries. However, the roles of NE in adventitial fibroblasts (AFs) are unknown. This study investigated the roles of NE in regulating AFs-derived extracellular vesicles (EVs) release and vascular smooth muscle cells (VSMCs) proliferation in
hypertension. Methods: AFs and VSMCs were prepared from aorta of Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). AFs were treated with NE (10 μM) for 24 h (every 6 h, 4 times), and cultured in exosomes-depleted medium for 48 h. EVs were isolated from AFs medium with ultracentrifugation for identification and transfer to VSMCs. Results: NE promoted AFs phenotypic transformation and proliferation, which were prevented by α-receptor antagonist
phentolamine rather than β-receptor antagonist
propranolol. NE-treated AFs
conditioned medium stimulated VSMCs proliferation, which was inhibited by either exosome inhibitor
GW4869 or
phentolamine. NE increased small EVs number, diameter and
angiotensin converting enzyme (ACE) contents. The NE-induced EVs release was abolished by
GW4869. The EVs from NE-treated AFs stimulated VSMCs proliferation, which was prevented by
angiotensin II type 1 receptor antagonist losartan. The EVs from the ACE knockdown-treated AFs showed lower ACE contents, and lost their roles in stimulating VSMCs proliferation. Conclusion: NE promotes AFs-derived small EVs release and ACE transfer, and then causes VSMCs proliferation in
hypertension. Intervention of AFs-derived EVs release may be potential
therapeutics for excessive sympathetic activation-related
vascular remodeling in
hypertension.