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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.

SUBMITTER: Kofler NM

PROVIDER: S-EPMC4643246 | biostudies-other | 2015 Nov

REPOSITORIES: biostudies-other

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Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations.

Kofler Natalie M NM Cuervo Henar H Uh Minji K MK Murtomäki Aino A Kitajewski Jan J

Scientific reports 20151113

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 endotheli ...[more]

PMID: 26563570

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Project description:Although mitochondrial activity is critical for angiogenesis, its mechanism is not entirely clear. Here, we investigate the angiogenic functions of three separate nuclear genes that encode for mitochondrial proteins, including mitochondrial transcriptional factor (TFAM), respiratory complex IV component (COX10), and a mitochondrial redox protein thioredoxin 2 (TRX2), which are responsible for distinct mitochondrial functions. We aim to investigate if mitochondrial activities regulate common endothelial cell (EC) signaling pathways during angiogenesis. The silencing of Tfam, Cox10, or Trx2 in an in vitro 3D sprouting assay attenuates EC sprouting, which correlated with reduced EC proliferation but not with ROS generation or EC apoptosis. Mice with an inducible deletion of Tfam, Cox10, or Trx2 exhibit retarded retinal vessel growth without penetration into the deep plexi at early ages (P5-P12). The three mutant mice develop arteriovenous malformations (AVM) with microaneurysm formation in the microvessels at advanced ages (P12-P30); the hypovasculature and microaneurysm phenotypes resemble that of aged human retinas and human primitive retinal vascular abnormalities such as Coats’ disease, Leber’s military aneurysms and familial exudative vitreoretinopathy. Single-cell RNA-seq analyses of retinal ECs suggest that the three mutant mice have common EC clusters with reduced gene expressions in anion transporters, actin organization, extracellular matrix, and angiogenesis. These EC clusters also have increased gene expressions in endothelial-mesenchymal transition and arterial markers, correlating with enhanced TGFbR signaling in Tfam, Cox10, or Trx2-deficient mice. Importantly, pharmacological blockade by TGFbR inhibitors attenuated retinal vessel growth retardation and AVM formation in all three mutant mice. Our study demonstrates that mitochondrial dysfunction induces TGF-b receptor-mediated arteriovenous malformations and microaneurysm formation in mouse retinas, and provide a novel model and therapeutic intervention for human primitive retinal vascular abnormalities, which are characterized by retinal vascular malformations and are associated with many pathological complications such as diabetes and hypertension that can result in vision loss.

Dataset Information

Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations.

Publications

Combined deficiency of Notch1 and Notch3 causes pericyte dysfunction, models CADASIL, and results in arteriovenous malformations.

Similar Datasets

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