医学
帕博西利布
内皮干细胞
癌症研究
血管内皮生长因子B
细胞周期检查点
ACVRL1型
细胞周期
血管内皮生长因子
内皮糖蛋白
血管内皮生长因子A
细胞生物学
免疫学
生物
内科学
癌症
干细胞
遗传学
血管内皮生长因子受体
体外
乳腺癌
转移性乳腺癌
川地34
作者
Gaël Genet,Nafiisha Genet,Umadevi Paila,Shelby Cain,Aleksandra Cwiek,Nicholas W. Chavkin,Vlad Serbulea,Agnès Figueras,Pau Cerdà,Stephanie P. McDonnell,Danya Sankaranarayanan,Mahalia Huba,Elizabeth A. Nelson,Antoni Riera‐Mestre,Karen K. Hirschi
出处
期刊:Circulation
[Ovid Technologies (Wolters Kluwer)]
日期:2023-12-21
标识
DOI:10.1161/circulationaha.122.062952
摘要
BACKGROUND: Distinct endothelial cell cycle states (early G1 versus late G1) provide different “windows of opportunity” to enable the differential expression of genes that regulate venous versus arterial specification, respectively. Endothelial cell cycle control and arteriovenous identities are disrupted in vascular malformations including arteriovenous shunts, the hallmark of hereditary hemorrhagic telangiectasia (HHT). To date, the mechanistic link between endothelial cell cycle regulation and the development of arteriovenous malformations (AVMs) in HHT is not known. METHODS: We used BMP (bone morphogenetic protein) 9/10 blocking antibodies and endothelial-specific deletion of activin A receptor like type 1 ( Alk1 ) to induce HHT in Fucci (fluorescent ubiquitination-based cell cycle indicator) 2 mice to assess endothelial cell cycle states in AVMs. We also assessed the therapeutic potential of inducing endothelial cell cycle G1 arrest in HHT to prevent AVMs by repurposing the Food and Drug Administration–approved CDK (cyclin-dependent kinase) 4/6 inhibitor (CDK4/6i) palbociclib. RESULTS: We found that endothelial cell cycle state and associated gene expressions are dysregulated during the pathogenesis of vascular malformations in HHT. We also showed that palbociclib treatment prevented AVM development induced by BMP9/10 inhibition and Alk1 genetic deletion. Mechanistically, endothelial cell late G1 arrest induced by palbociclib modulates the expression of genes regulating arteriovenous identity, endothelial cell migration, metabolism, and VEGF-A (vascular endothelial growth factor A) and BMP9 signaling that collectively contribute to the prevention of vascular malformations. CONCLUSIONS: This study provides new insights into molecular mechanisms leading to HHT by defining how endothelial cell cycle is dysregulated in AVMs because of BMP9/10 and Alk1 signaling deficiencies, and how restoration of endothelial cell cycle control may be used to treat AVMs in patients with HHT.
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