Promoting vascular stability through Src inhibition and Tie2 activation: A model-based analysis
Summary: Dysregulated angiogenesis signaling leads to pathological vascular growth and leakage, and is a hallmark of many diseases including cancer and ocular diseases. In peripheral arterial disease, the concomitant increase in vascular permeability presents significant challenges in therapeutic ef...
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| Format: | Article |
| Language: | English |
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Elsevier
2025-06-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225008867 |
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| author | Yu Zhang Christopher D. Kontos Brian H. Annex Aleksander S. Popel |
| author_facet | Yu Zhang Christopher D. Kontos Brian H. Annex Aleksander S. Popel |
| author_sort | Yu Zhang |
| collection | DOAJ |
| description | Summary: Dysregulated angiogenesis signaling leads to pathological vascular growth and leakage, and is a hallmark of many diseases including cancer and ocular diseases. In peripheral arterial disease, the concomitant increase in vascular permeability presents significant challenges in therapeutic efforts to improve perfusion by stimulating vascular growth. Building a mechanistic understanding of the endothelial control of vascular growth and permeability signaling is crucial to guide our efforts to identify therapeutic strategies that permit blood vessel growth while maintaining vascular stability. We develop a mechanistic systems biology model of the endothelial signaling network formed by the vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-Tie pathways, two major signaling pathways regulating vascular growth and stability. Our model, calibrated and validated against experimental data, reveals the mechanisms through which chronic Ang1 stimulation protects endothelial cells from VEGF-induced hyperpermeability, and predicts that combining Src inhibition with Tie2 activation can inhibit vascular leakage without disturbing angiogenesis signaling. |
| format | Article |
| id | doaj-art-90ecd8a0b7994e0fb61f80fdfa3adfec |
| institution | DOAJ |
| issn | 2589-0042 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-90ecd8a0b7994e0fb61f80fdfa3adfec2025-08-20T03:13:03ZengElsevieriScience2589-00422025-06-0128611262510.1016/j.isci.2025.112625Promoting vascular stability through Src inhibition and Tie2 activation: A model-based analysisYu Zhang0Christopher D. Kontos1Brian H. Annex2Aleksander S. Popel3Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21215, USA; Corresponding authorDepartment of Medicine, Duke University Medical Center, Durham, NC 27710, USADepartment of Medicine, Augusta University, Augusta, GA 30912, USADepartment of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, MD 21215, USASummary: Dysregulated angiogenesis signaling leads to pathological vascular growth and leakage, and is a hallmark of many diseases including cancer and ocular diseases. In peripheral arterial disease, the concomitant increase in vascular permeability presents significant challenges in therapeutic efforts to improve perfusion by stimulating vascular growth. Building a mechanistic understanding of the endothelial control of vascular growth and permeability signaling is crucial to guide our efforts to identify therapeutic strategies that permit blood vessel growth while maintaining vascular stability. We develop a mechanistic systems biology model of the endothelial signaling network formed by the vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-Tie pathways, two major signaling pathways regulating vascular growth and stability. Our model, calibrated and validated against experimental data, reveals the mechanisms through which chronic Ang1 stimulation protects endothelial cells from VEGF-induced hyperpermeability, and predicts that combining Src inhibition with Tie2 activation can inhibit vascular leakage without disturbing angiogenesis signaling.http://www.sciencedirect.com/science/article/pii/S2589004225008867Natural sciencesBiological sciencesBioinformaticsPharmacoinformatics |
| spellingShingle | Yu Zhang Christopher D. Kontos Brian H. Annex Aleksander S. Popel Promoting vascular stability through Src inhibition and Tie2 activation: A model-based analysis iScience Natural sciences Biological sciences Bioinformatics Pharmacoinformatics |
| title | Promoting vascular stability through Src inhibition and Tie2 activation: A model-based analysis |
| title_full | Promoting vascular stability through Src inhibition and Tie2 activation: A model-based analysis |
| title_fullStr | Promoting vascular stability through Src inhibition and Tie2 activation: A model-based analysis |
| title_full_unstemmed | Promoting vascular stability through Src inhibition and Tie2 activation: A model-based analysis |
| title_short | Promoting vascular stability through Src inhibition and Tie2 activation: A model-based analysis |
| title_sort | promoting vascular stability through src inhibition and tie2 activation a model based analysis |
| topic | Natural sciences Biological sciences Bioinformatics Pharmacoinformatics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004225008867 |
| work_keys_str_mv | AT yuzhang promotingvascularstabilitythroughsrcinhibitionandtie2activationamodelbasedanalysis AT christopherdkontos promotingvascularstabilitythroughsrcinhibitionandtie2activationamodelbasedanalysis AT brianhannex promotingvascularstabilitythroughsrcinhibitionandtie2activationamodelbasedanalysis AT aleksanderspopel promotingvascularstabilitythroughsrcinhibitionandtie2activationamodelbasedanalysis |