Deficiency of Notch signaling in pericytes results in arteriovenous malformations.

Taliha Nadeem,Bianca Bigit,Wil Bogue,Henar Cuervo

doi:10.1172/jci.insight.125940

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.

Highlights

Arteriovenous malformations (AVMs) are focal vascular lesions where arteries shunt directly to veins without an intervening capillary bed
To investigate the function of Notch signaling in pericytes, we generated perivascular-specific Rbpj conditional KO mice by crossing platelet derived growth factor receptor-β (PDGFRβ)-P2A-CreERT2 transgenic mice [22] with Rbpjtm1Hon (Rbpjflox) mice [23]
PDGFRβ-P2A-CreERT2 mice allow for tamoxifen-inducible expression of Cre-recombinase under the control of the platelet derived growth factor receptor-β (PDGFRβ) promoter, which is expressed in perivascular cells, and present a high recombination efficiency in the retina and brain [22]

Summary

Introduction

Arteriovenous malformations (AVMs) are focal vascular lesions where arteries shunt directly to veins without an intervening capillary bed. These lesions can occur in several organs but are harmful in the brain, where they can result in seizures, stroke, and death [1]. Despite their devastating consequences, the cellular and molecular basis of AVM formation is poorly understood. Vascular mural cells are support cells in vessel function. There are 2 types of mural cells: pericytes and vascular smooth muscle cells (vSMCs). Failure to recruit pericytes results in endothelial cell (EC) hyperplasia, blood vessel dilation, microaneurysm development, and edema [5]

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