Notch-1 signalling is activated in brain arteriovenous malformations in humans

Abstract

A role for the Notch signalling pathway in the formation of arteriovenous malformations during development has been suggested. However, whether Notch signalling is involved in brain arteriovenous malformations in humans remains unclear. Here, we performed immunohistochemistry on surgically resected brain arteriovenous malformations and found that, compared with control brain vascular tissue, Notch-1 signalling was activated in smooth muscle and endothelial cells of the lesional tissue. Western blotting showed an activated form of Notch-1 in brain arteriovenous malformations, irrespective of clinical presentation and with or without preoperative embolization, but not in normal cerebral vessels from controls. In addition, the Notch-1 ligands Jagged-1 and Delta-like-4 and the downstream Notch-1 target Hes-1 were increased in abundance and activated in human brain arteriovenous malformations. Finally, increased angiogenesis was found in adult rats treated with a Notch-1 activator. Our findings suggest that activation of Notch-1 signalling is a phenotypic feature of brain arteriovenous malformations, and that activation of Notch-1 in normal vasculature induces a pro-angiogenic state, which may contribute to the development of vascular malformations.

Radiosurgery inhibition of the Notch signaling pathway in a rat model of arteriovenous malformations

“…36 Activation of Notch1 signaling has been reported to result in vessel enlargement and arteriovenous communication. 27,70 Notch4 signaling was also activated through interaction with Delta-like1, Delta-like4, and Jagged1 in the endothelial cells of an AVM model. Previous studies have demonstrated that increasing Notch4 activation in the mouse vasculature produces dilated vessels and reduces smooth muscle cell populations and arteriovenous communications within the cerebral circulation.…”

“…43,70 Activation of Notch1 or Notch4 in mice causes AVM-like abnormalities. 7,27,42,43 Recently, normalization of Notch4 has been suggested as a strategy to reduce blood vessel size in a mouse model of AVMs.…”

“…It has been reported that the Notch signaling pathway responds to the Notch1 activator by increased angiogenesis and Jagged1 inhibitor by reduced angiogenesis in adult rats. 70 However, the knowledge of how the Notch signaling pathway responds to radiosurgery in AVM vessels remains absent in the literature. This study was undertaken to examine whether radiosurgery inhibits endothelial Notch signaling and molecular mechanisms of radiosurgical obliteration of "nidus" vessels in a rat model of AVMs.…”

Constitutively active Notch4 receptor elicits brain arteriovenous malformations through enlargement of capillary-like vessels

“…Abnormal signaling induces enlarged AV connections and shunting in mouse and zebrafish embryos (12)(13)(14). Notch activity is aberrantly increased in the endothelium of human brain AVMs (18,20), suggesting that it may participate in the growth or maintenance of human AVMs. These findings offer exciting opportunities to understand the molecular mechanisms of AVM formation.…”

Caroli Disease Associated With Vein of Galen Malformation in a Male Child

“…It is also suggested that activation of Notch 1 and its ligand Jagged 1 in normal vessels induces abnormal angiogenesis, leading to AVM formation. 14 Notch signaling and especially the interaction with its downstream ligand Jagged 1 are also essential for adequate development of the intrahepatic bile ducts. 15 Mutations of Jagged 1, for example, result in a lack of intrahepatic bile ducts, called Alagille syndrome.…”