Theranostics 2022; 12(10):4718-4733. doi:10.7150/thno.70974 This issue

Research Paper

Norepinephrine acting on adventitial fibroblasts stimulates vascular smooth muscle cell proliferation via promoting small extracellular vesicle release

Chao Ye1, Fen Zheng1, Tao Xu1, Nan Wu1, Ying Tong1, Xiao-Qing Xiong1, Ye-Bo Zhou1, Jue-Jin Wang1, Qi Chen2, Yue-Hua Li2, Guo-Qing Zhu1✉, Ying Han1✉

1. Key Laboratory of Targeted Intervention of Cardiovascular Disease, Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, and Department of Physiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.
2. Department of Pathophysiology, Nanjing Medical University, Nanjing, Jiangsu 211166, China.

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Citation:
Ye C, Zheng F, Xu T, Wu N, Tong Y, Xiong XQ, Zhou YB, Wang JJ, Chen Q, Li YH, Zhu GQ, Han Y. Norepinephrine acting on adventitial fibroblasts stimulates vascular smooth muscle cell proliferation via promoting small extracellular vesicle release. Theranostics 2022; 12(10):4718-4733. doi:10.7150/thno.70974. Available from https://www.thno.org/v12p4718.htm

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Abstract

Graphic abstract

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.

Keywords: norepinephrine, extracellular vesicle, hypertension, adventitial fibroblasts, vascular smooth muscle cell, angiotensin converting enzyme