title: Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations.
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.
authors.affiliation: Department of Ob/Gyn, Columbia University, New York, NY 10032, USA.
authors.forename: Natalie M
authors.initials: NM
authors.lastname: Kofler
authors.affiliation: Department of Ob/Gyn, Columbia University, New York, NY 10032, USA.
authors.forename: Henar
authors.initials: H
authors.lastname: Cuervo
authors.affiliation: Department of Ob/Gyn, Columbia University, New York, NY 10032, USA.
authors.forename: Minji K
authors.initials: MK
authors.lastname: Uh
authors.affiliation: Department of Ob/Gyn, Columbia University, New York, NY 10032, USA.|Division of Genetics, Biosciences, Viikki Biocenter, University of Helsinki, POB 56, FIN-00014, Helsinki, Finland.
authors.forename: Aino
authors.initials: A
authors.lastname: Murtomäki
authors.affiliation: Department of Ob/Gyn, Columbia University, New York, NY 10032, USA.|Pathology, Columbia University, New York, NY 10032, USA.|Herbert Irving Comprehensive Cancer Center, Columbia University, 1130 St. Nicholas Ave, New York, NY 10032, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Kitajewski
mesh_terms: D000818:Animals; D001165:Arteriovenous Malformations / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D046589:CADASIL / Q000235:genetics* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D020286:Pericytes / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics*; D000071656:Receptor, Notch3; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000172:deficiency / Q000235:genetics*; D012171:Retinal Vessels / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: C497762:Notch1 protein, mouse; C499373:Notch3 protein, mouse; D051881:Receptor, Notch1; D000071656:Receptor, Notch3; D051880:Receptors, Notch; D020797:Receptor, Platelet-Derived Growth Factor beta; D020778:Matrix Metalloproteinase 2