Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature
10 affiliations
- 1Department of Cell Biology and
- 2Developmental Genomics Center
- 3Robert M. Berne Cardiovascular Research Center
- 4Comprehensive Cancer Center
- 5Departments of Molecular Physiology and Biophysics, and
- 6Biomedical Engineering, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
- 7Department of Pediatrics, Division of Cardiology, University of Washington School of Medicine, Seattle, Washington, USA.
- 8Center for Developmental Biology and Regenerative Medicine, Seattle Children’s Research Institute, Seattle, Washington, USA.
- 9Radiology and Medical Imaging, and
- 10Microbiology, Immunology and Cancer Biology, University of Virginia School of Medicine, Charlottesville, Virginia, USA.
Abstract
Dysfunctional tumor vessels promote disease progression, whereas improved function enhances therapeutic delivery. However, current approaches to normalize tumor vasculature have limited efficacy. In vascular malformations, vessels are similarly dysfunctional, with endothelial cell (EC) hyperproliferation impairing arterial-venous specification. These defects are corrected with palbociclib, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) that has beneficial effects on tumor and immune cells, but the effects on tumor vasculature are not well characterized. In our studies, murine mammary tumor ECs (TECs) exhibited disrupted cell cycle and specification, and CDK4/6i promoted TEC cycle control, enabling improved tumor vascular function. To investigate transcriptomic changes, we performed single-cell RNA sequencing (scRNA-seq) of treated and untreated tumors, and healthy tissues. CDK4/6i-mediated TEC cycle arrest promoted arterial-venous specification, cellular junctions, and pericyte association, and suppressed glycolytic and immunosuppressive gene expression. These effects were associated with increased vessel perfusion, decreased tumor hypoxia, and a more favorable immune landscape with immunotherapy. In scRNA-seq datasets from patients treated long-term with CDK4/6i, TECs exhibited similar transcriptomic changes associated with arterial-venous specification, pericyte recruitment, and immune signaling. Thus, in contrast to current strategies, CDK4/6i-mediated vascular changes may be maintained with continued treatment, highlighting the relevance of modulating TEC cycle to improve vessel maturation/function.
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BibTeX
@article{cain2026endothelial,
title = {{Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature}},
author = {Shelby R. Cain and Gael Genet and Nafiisha Genet and Jordon W. Aragon and Madeline G. Jackson and Victoria M. Milosek and Mark R. Schwartz and Umadevi Paila and Aleksandra Cwiek and Zaneta Markowska and Nicholas W. Chavkin and Richard J. Price and Andrew C. Dudley and Karen K. Hirschi},
journal = {JCI Insight},
year = {2026},
month = sep,
doi = {10.1172/jci.insight.203732},
url = {https://doi.org/10.1172/jci.insight.203732},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Endothelial cell cycle inhibition enables blood vessel maturation to normalize the tumor vasculature
AU - Shelby R. Cain
AU - Gael Genet
AU - Nafiisha Genet
AU - Jordon W. Aragon
AU - Madeline G. Jackson
AU - Victoria M. Milosek
AU - Mark R. Schwartz
AU - Umadevi Paila
AU - Aleksandra Cwiek
AU - Zaneta Markowska
AU - Nicholas W. Chavkin
AU - Richard J. Price
AU - Andrew C. Dudley
AU - Karen K. Hirschi
PY - 2026
DA - 2026/09/10
JO - JCI Insight
DO - 10.1172/jci.insight.203732
UR - https://doi.org/10.1172/jci.insight.203732
AB - Dysfunctional tumor vessels promote disease progression, whereas improved function enhances therapeutic delivery. However, current approaches to normalize tumor vasculature have limited efficacy. In vascular malformations, vessels are similarly dysfunctional, with endothelial cell (EC) hyperproliferation impairing arterial-venous specification. These defects are corrected with palbociclib, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) that has beneficial effects on tumor and immune cells, but the effects on tumor vasculature are not well characterized. In our studies, murine mammary tumor ECs (TECs) exhibited disrupted cell cycle and specification, and CDK4/6i promoted TEC cycle control, enabling improved tumor vascular function. To investigate transcriptomic changes, we performed single-cell RNA sequencing (scRNA-seq) of treated and untreated tumors, and healthy tissues. CDK4/6i-mediated TEC cycle arrest promoted arterial-venous specification, cellular junctions, and pericyte association, and suppressed glycolytic and immunosuppressive gene expression. These effects were associated with increased vessel perfusion, decreased tumor hypoxia, and a more favorable immune landscape with immunotherapy. In scRNA-seq datasets from patients treated long-term with CDK4/6i, TECs exhibited similar transcriptomic changes associated with arterial-venous specification, pericyte recruitment, and immune signaling. Thus, in contrast to current strategies, CDK4/6i-mediated vascular changes may be maintained with continued treatment, highlighting the relevance of modulating TEC cycle to improve vessel maturation/function.
SN - 2379-3708
ER -