Abstract
Pericytes regulate vessel stability and pericyte dysfunction contributes to retinopathies, stroke, and cancer. Here we define Notch as a key regulator of pericyte function during angiogenesis. In Notch1+/−; Notch3−/− mice, combined deficiency of Notch1 and Notch3 altered pericyte interaction with the endothelium and reduced pericyte coverage of the retinal vasculature. Notch1 and Notch3 were shown to cooperate to promote proper vascular basement membrane formation and contribute to endothelial cell quiescence. Accordingly, loss of pericyte function due to Notch deficiency exacerbates endothelial cell activation caused by Notch1 haploinsufficiency. Mice mutant for Notch1 and Notch3 develop arteriovenous malformations and display hallmarks of the ischemic stroke disease CADASIL. Thus, Notch deficiency compromises pericyte function and contributes to vascular pathologies.
Highlights
Domain is released from the plasma membrane by two proteolytic cleavage events, the final mediated by gamma-secretase
Notch[3] signaling regulates vascular smooth muscle cell differentiation, less is known about the role of Notch receptors in pericytes[35]
Expression of Jagged[1] by both pericytes and endothelial cells in the developing retinal vasculature (Supplemental Fig. S1D) suggested that Jagged[1] regulates Notch-dependent endothelial/pericyte crosstalk during angiogenesis
Summary
Domain is released from the plasma membrane by two proteolytic cleavage events, the final mediated by gamma-secretase. The Notch intracellular domain translocates to the nucleus to form a complex with CSL (CBF-1, suppressor of Hairless, LAG-1)/RBPjκ and Mastermind-like proteins (MAML)[15,16] This complex activates transcription of canonical Notch target genes, including Hes and Hey transcriptional repressors, PDGFR-β , and smooth muscle α -actin (α SMA)[17,18,19,20]. We assessed retinal angiogenesis in mice with combined deficiency of Notch[1] and Notch[3] and found that Notch signaling was required for proper pericyte coverage and interaction with the endothelium. Pericyte dysfunction due to Notch[1] and Notch[3] deficiency, and endothelial activation as a result of Notch[1] haploinsufficiency caused retinal hyper-vascularization and vascular pathologies. Notch1+/−; Notch3−/− mice present with an accelerated CADASIL phenotype in developing retinal blood vessels and arteriovenous malformations
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