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CDK6-mediated endothelial cell cycle acceleration drives arteriovenous malformations in hereditary hemorrhagic telangiectasia

Lookup NU author(s): Emerita Professor Helen Arthur

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Abstract

© The Author(s), under exclusive licence to Springer Nature Limited 2024.Increased endothelial cell proliferation is a hallmark of arteriovenous malformations (AVMs) in hereditary hemorrhagic telangiectasia (HHT). Here, we report a cyclin-dependent kinase 6 (CDK6)-driven mechanism of cell cycle deregulation involved in endothelial cell proliferation and HHT pathology. Specifically, endothelial cells from the livers of HHT mice bypassed the G1/S checkpoint and progressed through the cell cycle at an accelerated pace. Phosphorylated retinoblastoma (pRB1)—a marker of G1/S transition through the restriction point—accumulated in endothelial cells from retinal AVMs of HHT mice and endothelial cells from skin telangiectasia samples from HHT patients. Mechanistically, inhibition of activin receptor-like kinase 1 signaling increased key restriction point mediators, and treatment with the CDK4/6 inhibitors palbociclib or ribociclib blocked increases in pRB1 and retinal AVMs in HHT mice. Palbociclib also improved vascular pathology in the brain and liver, and slowed cell cycle progression in endothelial cells and endothelial cell proliferation. Endothelial cell-specific deletion of CDK6 was sufficient to protect HHT mice from AVM pathology. Thus, clinically approved CDK4/6 inhibitors might have the potential to be repurposed for HHT.

Publication metadata

Author(s): Dinakaran S, Qutaina S, Zhao H, Tang Y, Wang Z, Ruiz S, Nomura-Kitabayashi A, Metz CN, Arthur HM, Meadows SM, Blanc L, Faughnan ME, Marambaud P

Publication type: Article

Publication status: Published

Journal: Nature Cardiovascular Research

Year: 2024

Volume: 3

Pages: 1301–1317

Print publication date: 01/11/2024

Online publication date: 01/11/2024

Acceptance date: 17/09/2024

ISSN (print): 2731-0590

Publisher: Springer

URL: https://doi.org/10.1038/s44161-024-00550-9

DOI: 10.1038/s44161-024-00550-9

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