Nerve growth factor (Ngf) gene-driven semaphorin 3a (Sema3a) expression exacerbates thoracic aortic aneurysm dissection in mice

Author:

Wu Li-Fei123,Zhou Ying12,Wang De-Ping12,Zhang Jiao-Jiao12,Zheng Zhi-Fa4,Guo Jia5,Shen Jing12,Shi Jian-Yun12,Liu Qing-Hua13,Wang Xue-Ning4,Wang Hai-Xiong6,Du Wen-Jing7,Li Miao-Ling8,Cao Ji-Min12

Affiliation:

1. Key Laboratory of Cellular Physiology at Shanxi Medical University, Ministry of Education

2. Department of Physiology, Shanxi Medical University

3. Department of Pathophysiology, Shanxi Medical University

4. Department of Cardiovascular Surgery, Shanxi Bethune Hospital

5. Center for Hypertension Care, Shanxi Medical University First Hospital

6. Department of Cardiology, Shanxi Cardiovascular Hospital, Taiyuan,

7. State Key Laboratory of Medical Molecular Biology, Department of Cell Biology, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing

8. Key Laboratory of Medical Electrophysiology at Southwest Medical University, Ministry of Education, and the Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China

Abstract

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease and currently there is no pharmacological therapy. Sympathetic nerve overactivity plays an important role in the development of TAAD. Sympathetic innervation is mainly controlled by nerve growth factor (NGF, a key neural chemoattractant) and semaphoring 3A (Sema3A, a key neural chemorepellent), while the roles of these two factors in aortic sympathetic innervation and especially TAAD are unknown. We hypothesized that genetically manipulating the NGF/Sema3A ratio by the Ngf-driven Sema3a expression approach may reduce aortic sympathetic nerve innervation and mitigate TAAD progression. A mouse strain of Ngf gene-driven Sema3a expression (namely Ngf Sema3a/Sema3a mouse) was established by inserting the 2A-Sema3A expression frame to the Ngf terminating codon using CRISPR/Cas9 technology. TAAD was induced by β-aminopropionitrile monofumarate (BAPN) both in Ngf Sema3a/Sema3a mice and wild type (WT) littermates. Contrary to our expectation, the BAPN-induced TAAD was severer in Ngf Sema3a/Sema3a mice than in wild-type (WT) mice. In addition, Ngf Sema3a/Sema3a mice showed higher aortic sympathetic innervation, inflammation and extracellular matrix degradation than the WT mice after BAPN treatment. The aortic vascular smooth muscle cells isolated from Ngf Sema3a/Sema3a mice and pretreated with BAPN in vivo for two weeks showed stronger capabilities of proliferation and migration than that from the WT mice. We conclude that the strategy of Ngf-driven Sema3a expression cannot suppress but worsens the BAPN-induced TAAD. By investigating the aortic phenotype of Ngf Sema3a/Sema3a mouse strain, we unexpectedly find a path to exacerbate BAPN-induced TAAD which might be useful in future TAAD studies.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology,Internal Medicine

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