Sajeth Dinakaran, Sima Qutaina, Haitian Zhao, Yuefeng Tang, Zhimin Wang, Santiago Ruiz, Aya Nomura-Kitabayashi, Christine N. Metz, Helen M. Arthur, Stryder M. Meadows, Lionel Blanc, Marie E. Faughnan, Philippe Marambaud
Feinstein Institutes for Medical Research and Northwell Health. Donald and Barbara Zucker School of Medicine at Hofstra/Northwell. Institut Pasteur de Montevideo. Newcastle University. Tulane University. Cohen Children’s Medical Center. St. Michael’s Hospital. University of Toronto.
United States, Uraguay and Canada
Nature Cardiovascular Research
Nat Cardiovas Res 2024; 3: 1301-1317
DOI: 10.1038/s44161-024-00550-9
Abstract
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.
Category
Pulmonary Arteriovenous Malformations
Genetic Factors Associated with Pulmonary Vascular Disease
Animal Models of Pulmonary Vascular Disease and Therapy
Medical Therapy. Efficacy or Lack of Efficacy
Age Focus: No Age-Related Focus
Fresh or Filed Publication: Fresh (PHresh). Less than 1-2 years since publication
Article Access
Free PDF File or Full Text Article Available Through PubMed or DOI: No