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Endothelial cyclin I reduces vulnerability to angiotensin II-induced vascular remodeling and abdominal aortic aneurysm risk.

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机构： [1]Department of Cardiovascular Surgery, The First People's Hospital of Yunnan Province, China [2]The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China [3]Department of Hematopathology, The First People's Hospital of Yunnan Province, China

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Retinoblastoma protein (Rb) supports vasoprotective E2F Transcription Factor 1 (E2f1)/Dihydrofolate Reductase (Dhfr) pathway activity in endothelial cells. Cyclin I (Ccni) promotes Cyclin-Dependent Kinase-5 (Cdk5)-mediated Rb phosphorylation. Therefore, we hypothesized that endothelial Ccni may regulate cardiovascular homeostasis, vessel remodeling, and abdominal aortic aneurysm (AAA) formation.Aortic CCNI mRNA expression was analyzed in the Gene Expression Omnibus (GEO) GSE57691 cohort consisting of AAA patients (n = 39) and healthy controls (n = 10). We employed wild-type (WT) mice and endothelial Ccni knockout (Ccnifl/flTie2-Cre) mice to conduct in vivo and ex vivo experimentation using an Angiotensin (Ang) II hypertension model and a CaCl2 AAA model. Mice were assessed for Rb/E2f1/Dhfr signaling, biopterin (i.e., biopterin [B], dihydrobiopterin [BH2], and tetrahydrobiopterin [BH4]) production, cardiovascular homeostasis, vessel remodeling, and AAA formation.Aortic CCNI mRNA expression was downregulated in AAA patients. Both Ang II- and CaCl2-induced WT mice showed aortic Ccni upregulation coupled with vasculoprotective upregulation of Rb/E2f1/Dhfr signaling and biopterins. Endothelial Ccni knockout downregulated medial Rb/E2f1/Dhfr signaling and biopterins in Ang II-induced hypertensive mice, which exacerbated eNos uncoupling and H2O2 production. Endothelial Ccni knockout impaired in vivo hemodynamic responses and endothelium-dependent vasodilatation in ex vivo mesenteric arteries in response to Ang II. Endothelial Ccni knockout exacerbated mesenteric artery remodeling and AAA risk in response to Ang II and CaCl2.Endothelial Ccni acts as a critical negative regulator of eNos uncoupling-mediated ROS generation and thereby reduces vulnerability to hypertension-induced vascular remodeling and AAA development in mice.Copyright © 2022. Published by Elsevier Inc.

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出版当年[2022]版：

大类 | 3 区医学

小类 | 3 区外周血管病

最新[2023]版：

大类 | 4 区医学

小类 | 4 区外周血管病

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出版当年[2021]版：

Q2 PERIPHERAL VASCULAR DISEASE

最新[2023]版：

Q2 PERIPHERAL VASCULAR DISEASE

影响因子： 2.9 最新[2023版] 3 最新五年平均 3.75 出版当年[2021版] 3.378 出版当年五年平均 3.514 出版前一年[2020版] 3.1 出版后一年[2022版]

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第一作者机构： [1]Department of Cardiovascular Surgery, The First People's Hospital of Yunnan Province, China [2]The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China

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通讯作者：

通讯机构： [1]Department of Cardiovascular Surgery, The First People's Hospital of Yunnan Province, China [2]The Affiliated Hospital of Kunming University of Science and Technology, Kunming, Yunnan, China [*1]The First People's Hospital of Yunnan Province, No.157 Jinbi Road, Kunming, Yunnan, China.

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