The vascular development in the central nervous system (CNS) depends on a tightly regulated interaction between endothelial and perivascular cells. Perivascular cells, also known as mural cells, including pericytes and vascular smooth muscle cells (vSMCs), provide structural support and regulate blood flow. Among the different signalling pathways involved in the process, Notch pathway plays an important role in this cell-to-cell communication, acting as a key regulator in cell differentiation, vascular organization and stability. The main purpose of this study was to evaluate the effects of perivascular Notch receptor loss on vascular structure in the CNS, analyse how the loss of Notch 1, Notch 2 and Notch 3 influence pericyte coverage and vSMC identity and to compare the phenotypic outcomes of the different Notch knock-outs combinations.
For this purpose, the retina and the brain cortex of Mus musculus were analysed. Each organ was examined at different postnatal stages to ensure the optimal stage for vessel formation analysis: The retina at postnatal day 6 (P6) and the cerebral cortex at day 14 (P14). The delection of Notch receptors in perivascular cells was achieved using the genetic Cre-LoxP system. The Cre-recombinase was expressed under the PDGFRβ promoter and was inducible by 4OH-Tamoxifen (PDGFRβ-P2A-CreERT), combined with the iSuRe-HadCre reporter system, which includes tdTomato as a fluorescent reporter for recombination.
The results show a central role of Notch 1 and Notch 3 in pericyte development and the contribution of Notch 1, Notch 2 and Notch 3 in vascular smooth muscle cell (vSMC) identity, particularly in arteries. No significant changes were observed in de vascular density or diameter. The results and defects observed in the different genotypes were due to a target disruption in perivascular cells rather than secondary alterations due to defects in the vasculature.
The vascular development in the central nervous system (CNS) depends on a tightly regulated interaction between endothelial and perivascular cells. Perivascular cells, also known as mural cells, including pericytes and vascular smooth muscle cells (vSMCs), provide structural support and regulate blood flow. Among the different signalling pathways involved in the process, Notch pathway plays an important role in this cell-to-cell communication, acting as a key regulator in cell differentiation, vascular organization and stability. The main purpose of this study was to evaluate the effects of perivascular Notch receptor loss on vascular structure in the CNS, analyse how the loss of Notch 1, Notch 2 and Notch 3 influence pericyte coverage and vSMC identity and to compare the phenotypic outcomes of the different Notch knock-outs combinations.
For this purpose, the retina and the brain cortex of Mus musculus were analysed. Each organ was examined at different postnatal stages to ensure the optimal stage for vessel formation analysis: The retina at postnatal day 6 (P6) and the cerebral cortex at day 14 (P14). The delection of Notch receptors in perivascular cells was achieved using the genetic Cre-LoxP system. The Cre-recombinase was expressed under the PDGFRβ promoter and was inducible by 4OH-Tamoxifen (PDGFRβ-P2A-CreERT), combined with the iSuRe-HadCre reporter system, which includes tdTomato as a fluorescent reporter for recombination.
The results show a central role of Notch 1 and Notch 3 in pericyte development and the contribution of Notch 1, Notch 2 and Notch 3 in vascular smooth muscle cell (vSMC) identity, particularly in arteries. No significant changes were observed in de vascular density or diameter. The results and defects observed in the different genotypes were due to a target disruption in perivascular cells rather than secondary alterations due to defects in the vasculature. Read More
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