Counteracting Age-Related Netrin-1 Signaling Insufficiency Ameliorates Endothelial Cell Senescence and Angiogenesis Impairment

Author:

Yang Zhen12,Li Han12,Yan Dan12,Luo Pengcheng12,Guan Yuqi12,Luo Mandi12,Nie Hao12,Huang Yi12,Zhang Le12,Ruan Lei12,Yan Jinhua12,Zhang Cuntai12

Affiliation:

1. Department of Geriatrics, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China

2. Key Laboratory of Vascular Aging, Ministry of Education, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology , Wuhan , China

Abstract

Abstract Senescent cells that accumulate are regarded as promising therapeutic targets. However, senolytic therapy failed to achieve satisfactory results. We previously discovered that young human plasma improved vascular endothelial cell senescence, and UNC5B might be a novel intervention target. Netrin-1, as a natural ligand of UNC5B, plays roles in multiple age-related vascular disorders, but its involvement in aging is still unclear. Here, we observed a significant decrease in plasma Netrin-1 levels in old healthy subjects compared to the young. In vivo, adeno-associated-virus-mediated delivery of Netrin-1 into aged mice significantly improved functional recovery in a model of hindlimb ischemia, promoted angiogenesis in ischemic tissues, and activated the endothelial nitric oxide synthase. Furthermore, we revealed that low-dose Netrin-1 recombinant protein significantly reduced senescence-associated-β-galactosidase-positive cells, inhibited the P53 pathway, promoted cell migration, increased tubule formation, and elevated nitric oxide production in senescent endothelial cells. However, UNC5B inhibition blocked the pro-angiogenesis effect of low-dose Netrin-1 on senescent cells or aortic rings. In summary, this study depicts that modulating Netrin-1 signaling can result in improved vascular health and Netrin-1 may have therapeutic potential for age-related ischemic diseases.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

Publisher

Oxford University Press (OUP)

Subject

Geriatrics and Gerontology,Aging

Reference38 articles.

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2. Senolytics reduce coronavirus-related mortality in old mice;Camell,2021

3. Cellular senescence: defining a path forward;Gorgoulis,2019

4. Senolytic drugs: reducing senescent cell viability to extend health span;Robbins,2021

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