Endothelial Rbpj deletion normalizes Notch4-induced brain arteriovenous malformation in mice
| Autor: | Nielsen, Corinne M, Zhang, Xuetao, Raygor, Kunal, Wang, Shaoxun, Bollen, Andrew W, Wang, Rong A |
|---|---|
| Rok vydání: | 2023 |
| Předmět: |
Pediatric
Brain Diseases Notch4 Immunology Neurosciences Brain Tetracycline Nervous System Malformations Cardiovascular Medical and Health Sciences Anti-Bacterial Agents Arteriovenous Malformations Mice Good Health and Well Being Immunoglobulin J Recombination Signal Sequence-Binding Protein Animals Congenital Structural Anomalies 2.1 Biological and endogenous factors Endothelium Aetiology Receptor |
| Zdroj: | The Journal of experimental medicine, vol 220, iss 2 |
| Popis: | Upregulation of Notch signaling is associated with brain arteriovenous malformation (bAVM), a disease that lacks pharmacological treatments. Tetracycline (tet)-regulatable endothelial expression of constitutively active Notch4 (Notch4*tetEC) from birth induced bAVMs in 100% of mice by P16. To test whether targeting downstream signaling, while sustaining the causal Notch4*tetEC expression, induces AVM normalization, we deleted Rbpj, a mediator of Notch signaling, in endothelium from P16, by combining tet-repressible Notch4*tetEC with tamoxifen-inducible Rbpj deletion. Established pathologies, including AV connection diameter, AV shunting, vessel tortuosity, intracerebral hemorrhage, tissue hypoxia, life expectancy, and arterial marker expression were improved, compared with Notch4*tetEC mice without Rbpj deletion. Similarly, Rbpj deletion from P21 induced advanced bAVM regression. After complete AVM normalization induced by repression of Notch4*tetEC, virtually no bAVM relapsed, despite Notch4*tetEC re-expression in adults. Thus, inhibition of endothelial Rbpj halted Notch4*tetEC bAVM progression, normalized bAVM abnormalities, and restored microcirculation, providing proof of concept for targeting a downstream mediator to treat AVM pathologies despite a sustained causal molecular lesion. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|