Research Paper Volume 10, Issue 10 pp 2695—2708
Role of alternative splicing of VEGF-A in the development of atherosclerosis
- 1 Department of Cardiovascular Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai 200030, China
received: August 31, 2018 ; accepted: September 25, 2018 ; published: October 13, 2018 ;https://doi.org/10.18632/aging.101580
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Copyright: Zhao and Zhang. This is an open‐access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Vascular endothelial cell growth factor A (VEGF-A) signaling promotes the endothelial cell proliferation, macrophage infiltration and foam cell formation, which play pivotal roles in the pathogenesis of atherosclerosis (AS). However, the role of alternative splicing of VEGF here is not known. Here, ApoE (-/-) mice supplied high-fat diet (HFD mice) were used to generate AS, while ApoE (-/-) mice supplied with normal diet (NOR mice) were used as a control. Aortic endothelial cells (AECs) and infiltrated macrophages were purified and quantified by flow cytometry. Alternative splicing of VEGF and the regulator of VEGF splicing, SRPK1, were assessed by RT-qPCR and immunoblotting in both AECs and aortic macrophages. We found that HFD mice developed AS in 12 weeks, while the NOR did not. Compared to NOR mice, HFD mice possessed significantly more AECs and AEC proliferation, and had significantly more aortic infiltrated macrophages and more apoptosis of them. Significant shift of VEGF-A splicing to pro-angiogenic VEGF165 was detected in both AECs and macrophages from HFD mice, seemingly through upregulation of SRPK1. In vitro, SRPK1 overexpression significantly increased EC proliferation and macrophage apoptosis. Thus, our data suggest that alternative splicing of VEGF-A to pro-angiogenic VEGF165 may contribute to the development of AS.