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Endothelial retinoblastoma protein reduces abdominal aortic aneurysm development via promoting DHFR/NO pathway-mediated vasoprotection

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Abstract

Cardiovascular disease (CVD) is a major cause of global mortality. The proper functioning of the endothelial layer of arteries is crucial to cardiovascular health. Retinoblastoma protein (Rb), encoded by the Rb1 gene, has been shown to offer vasoprotective effects. Herein, we investigated endothelial Rb’s effects on arterial function using an endothelial-specific conditional Rb1 knockout (Rb cKO) mouse model. We found that Rb deficiency reduced dihydrofolate reductase (DHFR) activity and downstream NO production in mouse aortic endothelial cells and blocked arterial vasodilation in an endothelial DHFR-dependent manner. Rb deficiency also increased phenylephrine-triggered arterial vasoconstriction, BP levels, and pathological aortic remodeling without significantly affecting prostanoid synthesis. Employing an angiotensin II (AngII)-stimulated apolipoprotein E knockout (apoE −/−) mice fed a standard, non-atherogenic diet, Rb deficiency increased aortic diameter, stimulated abdominal aortic aneurysm (AAA) development, and reduced survival. These pathological responses to Rb deficiency in AngII-stimulated apoE−/− mice were rescued by DHFR overexpression. Cumulatively, our findings reveal that endothelial Rb positively impacts arterial function by supporting vasoprotective endothelial DHFR/NO pathway activity, leading to reduced AAA development.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant Nos. 81760059, 81560060) and The YunLing Scholars and Special Joint Program of Yunnan Province (Grant No. 2018FE001-181). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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  1. Yu Cao and Da ** Zhang

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  1. Yu Cao
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  2. Da **ong
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  3. Ruize Kong
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  4. Guolin Dai
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  5. Minghua Zhong
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  6. Li Li
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  7. **** Zhang
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  8. Lihong Jiang
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  9. Hongrong Li
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Contributions

YC and DX conceived and designed the study; RK, GLD, and MHZ performed the experimental procedures; LL, JPZ, LHJ, and HRL analyzed the data; LHJ and HRL drafted the manuscript.

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Correspondence to Lihong Jiang or Hongrong Li.

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Lihong Jiang and Hongrong Li are co corresponding authors.

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Cao, Y., **ong, D., Kong, R. et al. Endothelial retinoblastoma protein reduces abdominal aortic aneurysm development via promoting DHFR/NO pathway-mediated vasoprotection. Mol Cell Biochem 460, 29–36 (2019). https://doi.org/10.1007/s11010-019-03567-y

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