Inhibition of vascular adventitial remodeling by netrin-1 in diabetic rats

in Journal of Endocrinology
Authors:
Hui-Fang Wang Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China

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Qing-Qing Yu Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China

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Rui-Fang Zheng Xinjiang Key Laboratory of Uighur Medicines, Xinjiang Institute of Materia Medica, Urumqi, Xinjiang, China

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Ming Xu Department of Clinical Pharmacy, School of Preclinical Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, China

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Correspondence should be addressed to M Xu: mingxu@cpu.edu.cn
DOI:
https://doi.org/10.1530/JOE-19-0258
Volume/Issue:
Volume 244: Issue 3
Article Type:
Research Article
Page Range:
445–458
Online Publication Date:
Mar 2020
Copyright:
© 2020 Society for Endocrinology 2020
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Cardiovascular complications of type 2 diabetes mellitus (T2DM) are associated with vascular remodeling in the arteries. Perivascular sympathetic neurons release an abundance of trophic factors to regulate vascular function via a paracrine signaling. Netrin-1, a diffusible protein that can be secreted outside the cell, is one of common signals of ‘conversation’ between nerve and vessel. The present study investigated whether netrin-1 is a novel modulator of sympathetic neurons paracrine signaling and played a critical role in vascular adventitial remodeling under T2DM. Vascular adventitial remodeling was observed in adventitial fibroblasts (AFs) responding to netrin-1 deficiency in the supernatant from primary rat superior cervical ganglia (SCG) neurons, shown as AFs proliferation, migration, and collagen deposition. Conditioned medium from the high glucose (HG)-treated SCG neurons contributed to AFs remodeling, which was effectively alleviated by exogenous netrin-1 supplementation. Further, it was found that uncoordinated-5-B (Unc5b) was mainly expressed in AFs among netrin-1 specific receptors. Treatment of netrin-1 inhibited H2O2 production derived from NADPH oxidase 4 (NOX4) through the UNC5b/CAMP/PKA signal pathway in AFs remodeling. In vivo, aorta adventitial remodeling was accompanied with the downregulation of netrin-1 in the perivascular sympathetic nerve in T2DM rats. Such abnormalities were restored by netrin-1 intervention, which was associated with the inhibition of NOX4 expression in the aorta adventitia. In conclusion, netrin-1 is a novel modulator of sympathetic neurons paracrine signaling to maintain AFs function. Vascular adventitial remodeling was aggravated by sympathetic neurons paracrine signaling under hyperglycemia, which was ameliorated by netrin-1 treatment through the UNC5b/CAMP/PKA/NOX4 pathway.

Supplementary Materials

    • Supplementary Fig.1
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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2020 Society for Endocrinology 2020
Page(s):
14
Article Type:
Research Article
Received Date:
22 Nov 2019
Accepted Date:
16 Dec 2019
Print Publication Date:
01 Mar 2020
Online Publication Date:
Mar 2020
Keywords:
type 2 diabetes mellitus; vascular adventitial remodeling; SCG neurons; netrin-1; Nox4

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