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Deficiency of Notch signaling in pericytes results in arteriovenous malformations
Taliha Nadeem, … , Bianca Bigit, Henar Cuervo
Taliha Nadeem, … , Bianca Bigit, Henar Cuervo
Published November 5, 2020
Citation Information: JCI Insight. 2020;5(21):e125940. https://doi.org/10.1172/jci.insight.125940.
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Research Article Angiogenesis Vascular biology

Deficiency of Notch signaling in pericytes results in arteriovenous malformations

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Abstract

Arteriovenous malformations (AVMs) are high-flow lesions directly connecting arteries and veins. In the brain, AVM rupture can cause seizures, stroke, and death. Patients with AVMs exhibit reduced coverage of the vessels by pericytes, the mural cells of microvascular capillaries; however, the mechanism underlying this pericyte reduction and its association with AVM pathogenesis remains unknown. Notch signaling has been proposed to regulate critical pericyte functions. We hypothesized that Notch signaling in pericytes is crucial to maintain pericyte homeostasis and prevent AVM formation. We inhibited Notch signaling specifically in perivascular cells and analyzed the vasculature of these mice. The retinal vessels of mice with deficient perivascular Notch signaling developed severe AVMs, together with a significant reduction in pericytes and vascular smooth muscle cells (vSMC) in the arteries, while vSMCs were increased in the veins. Vascular malformations and pericyte loss were also observed in the forebrain of embryonic mice deficient for perivascular Notch signaling. Moreover, the loss of Notch signaling in pericytes downregulated Pdgfrb levels and increased pericyte apoptosis, pointing to a critical role for Notch in pericyte survival. Overall, our findings reveal a mechanism of AVM formation and highlight the Notch signaling pathway as an essential mediator in this process.

Authors

Taliha Nadeem, Wil Bogue, Bianca Bigit, Henar Cuervo

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Figure 1

Inhibition of perivascular Notch signaling at birth results in severe AVMs.

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Inhibition of perivascular Notch signaling at birth results in severe AV...
(A) Diagram of tamoxifen administration to postnatal control and RbpjiΔPC mice and analysis at 6 weeks. (B) Confocal images showing 6-week retinal vasculature stained with anti-CD31 (white). Right panels show higher magnification of boxed regions highlighting vascular malformations in the retina of RbpjiΔPC mice. Scale bars: 600 μm (left panels) and 300 μm (right panels). (C) Quantification of percentage of vessel area (n = 4), branching points/mm2 (n = 5), and vessel diameter (n = 6–8) in control and RbpjiΔPC mice. (D) Images of the vasculature perfused with blue latex compound. Perfused vessels were subsequently stained with Isolectin B4 (IB4) and detected using HRP streptavidin (n = 3). Boxed region highlights arteriovenous shunt. Scale bars: 600 μm. Box-and-whisker plots show median, minimum, and maximum values. Data were analyzed using unpaired 2-tailed t test with Welch’s correction. a, artery; c, capillary; and v, vein. *P < 0.05, **P < 0.01, ***P < 0.001.
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