Abstract
Sufficient vascular supply is indispensable for brain development and function, whereas dysfunctional blood vessels are associated with human diseases such as vascular malformations, stroke or neurodegeneration. Pericytes are capillary-associated mesenchymal cells that limit vascular permeability and protect the brain by preserving blood-brain barrier integrity. Loss of pericytes has been linked to neurodegenerative changes in genetically modified mice. Here, we report that postnatal inactivation of the Rbpj gene, encoding the transcription factor RBPJ, leads to alteration of cell identity markers in brain pericytes, increases local TGFβ signalling, and triggers profound changes in endothelial behaviour. These changes, which are not mimicked by pericyte ablation, imperil vascular stability and induce the acquisition of pathological landmarks associated with cerebral cavernous malformations. In adult mice, loss of Rbpj results in bigger stroke lesions upon ischemic insult. We propose that brain pericytes can acquire deleterious properties that actively enhance vascular lesion formation and promote pathogenic processes.
Highlights
Sufficient vascular supply is indispensable for brain development and function, whereas dysfunctional blood vessels are associated with human diseases such as vascular malformations, stroke or neurodegeneration
Despite early and efficient deletion of Rbpj with tamoxifen injection from postnatal day 1 (P1) to P3, the vascular lesions were restricted to the central nervous system (CNS) (Supplementary Fig. 1h), started to develop at P7, and were prominent by P10
Given the notorious differences in the phenotype elicited by Rbpj deletion in pericytes with respect to artery-associated smooth muscle cells (SMCs), we investigated the activation level of canonical Notch signalling by analyzing two different reporter mouse lines (CBF:H2B-Venus and Hey1-EGFP) in which fluorescent protein expression is Interestingly, both lines fail to show evidence for Notch signalling in brain pericytes during early stages of postnatal development (Supplementary Fig. 7a, b), whereas SMCs covering penetrating arterioles in the cortex or pial arteries in the brain surface show reporter expression (Supplementary Fig. 7c, d)
Summary
Sufficient vascular supply is indispensable for brain development and function, whereas dysfunctional blood vessels are associated with human diseases such as vascular malformations, stroke or neurodegeneration. We report that postnatal inactivation of the Rbpj gene, encoding the transcription factor RBPJ, leads to alteration of cell identity markers in brain pericytes, increases local TGFβ signalling, and triggers profound changes in endothelial behaviour. These changes, which are not mimicked by pericyte ablation, imperil vascular stability and induce the acquisition of pathological landmarks associated with cerebral cavernous malformations. We report that loss of the transcription factor RBPJ alters fundamental aspects of brain pericyte identity, which involves increased contractility, capillary obstruction and the formation of aneurysms, increased TGFβ activation, haemorrhaging, and NVU dysfunction. We propose that pericytes can acquire disease-promoting properties, which lead to vascular malformations in the brain and increased tissue damage after ischaemic injury
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