The sympathetic transmitter norepinephrine inhibits VSMC proliferation induced by TGFβ by suppressing the expression of the TGFβ receptor ALK5 in aorta remodeling

The sympathetic system is involved in the arterial diseases, but its mechanism remains poorly understood. The present study aimed to explore the impact of the sympathetic neurotransmitter norepinephrine (NE) on transforming growth factor (TGF) β signaling and the role of NE in aortic remodeling. Guanethidine was used to induce a regional chemical sympathetic denervation (CSD) in angiotensin II (AngII) and β-aminopropionitrile (BAPN)-induced aortic aneurysm models. The diameter of the aorta was measured, and elastic fiber staining was performed. TGFβ type I receptor kinase (ALK5) expression in rat aortic NE-treated vascular smooth muscle cells (VSMCs) was detected by reverse transcription-quantitative PCR and western blotting. The effects of NE and ALK5 overexpression on migration, proliferation, apoptosis and TGFβ signaling were also evaluated. Furthermore, adrenergic receptor blockers were used to determine which receptor was involved in the modulation on TGFβ signaling by NE. The results of the present study demonstrated that CSD protected rats from AngII+BAPN-induced aortic remodeling and aneurysm formation. Compared with the control group, NE inhibited VSMC proliferation and migration, but promoted apoptosis by suppressing ALK5 expression, reversing the effects of TGFβ signaling through the suppression of the SMAD-dependent canonical pathway and promotion of the non-canonical pathway. These effects were prevented by ALK5 overexpression. The inhibition of α- or β-adrenergic receptors alleviated the NE-mediated suppression of ALK5 expression. In conclusion, regional CSD protected rats from aortic aneurysm. NE inhibited SMAD2/3-dependent TGFβ signaling by suppressing ALK5 expression, which may serve an important role in VSMC biological functions. Both α- and β-adrenergic receptors were involved in the regulation of ALK5 expression by NE. Abnormal sympathetic innervation of the aorta may be used as a therapeutic target in aortic diseases.