Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice

Abstract

Direct communication between arteries and veins without intervening capillary beds is the primary pathology of arteriovenous malformations (AVMs). Although Notch signaling is implicated in embryonic arteriovenous (AV) differentiation, its function in the adult mammalian vasculature has not been established due to the embryonic lethality that often occurs in both gain- and loss-of-function mutants. We expressed a constitutively active Notch4, int3, in the adult mouse endothelium by using the tetracycline-repressible system to suppress int3 during embryogenesis. int3 caused profound blood vessel enlargement and AV shunting, which are hallmarks of AVM, and led to lethality within weeks of its expression. Vessel enlargement, a manifestation of AVM, occurred in an apparently tissue-specific fashion; the liver, uterus, and skin were affected. int3-mediated vascular defects were accompanied by arterialization, including ectopic venous expression of ephrinB2, increased smooth muscle cells, and up-regulation of endogenous Notch signaling. Remarkably, the defective vessels and illness were reversed upon repression of int3 expression. Finally, endothelial expression of a constitutively active Notch1 induced similar hepatic vascular lesions. Our results provide gain-of-function evidence that Notch signaling in the adult endothelium is sufficient to render arterial characteristics and lead to AVMs

In vitro and in vivo arterial differentiation of human multipotent adult progenitor cells

“…Recent studies have, however, demonstrated the redundancy between Notch-1 and -4, supporting the notion that Notch-1 may be sufficient to induce arterial EC differentiation in hMAPCs. 51 The fact that not all arterial markers were elevated in hMAPCs under the influence of VEGF 165 (combined or not with Notch and patched ligands) and that arterial differentiation was not completely abrogated by Notch and/or Shh blocking may reflect the existence of additional VEGF/Notch/patched-independent pathways in arterial differentiation. We did, for instance, not fully explore the potential involvement of TGF-␤, COUP-TFII, adrenomedullin, or angiopoietins, known to play a role in AV fate decisions.…”

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

“…Expression of Notch was sufficient to induce vascular malformations even in adult mice, signifying the importance of Notch homeostasis. 88 After experiments on mice showed that Notch4 signaling is involved in AVM pathogenesis and Notch4 repression can lead to hemodynamic normalization, Murphy et al 89 studied the role of Notch in human brain AVMs. Using immunofluorescent staining, they showed that the presence of activated Notch1 is significantly higher in resected AVMs in comparison to autopsy and surgical biopsy controls.…”

Disruption of the transcription factor recombination signal-binding protein-Jκ (RBP-J) leads to veno-occlusive disease and interfered liver regeneration in mice

“…19 Notch signaling plays a pivotal role in the vascular system 20 by restricting endothelial tip cell specification 21 and specifying arterio-venous identity. 22 The disease genes responsible for CADASIL and Allagilles syndrome, both of which show inherited vascular anomalies, have been mapped to Notch3 and Jagged1, respectively, 20 suggesting a role in pathological angiogenesis. Indeed, blockade of Dll4 increases EC proliferation and tumor vascular density but inhibits tumor growth due to poor function of new vessels, a phenomenon defined as the Delta paradox.…”