Endothelial Notch4 signaling induces hallmarks of brain arteriovenous malformations in mice

PA Murphy, MTY Lam, X Wu, TN Kim… - Proceedings of the …, 2008 - National Acad Sciences
PA Murphy, MTY Lam, X Wu, TN Kim, SM Vartanian, AW Bollen, TR Carlson, RA Wang
Proceedings of the National Academy of Sciences, 2008National Acad Sciences
Brain arteriovenous malformations (BAVMs) can cause devastating stroke in young people
and contribute to half of all hemorrhagic stroke in children. Unfortunately, the pathogenesis
of BAVMs is unknown. In this article we show that activation of Notch signaling in the
endothelium during brain development causes BAVM in mice. We turned on constitutively
active Notch4 (int3) expression in endothelial cells from birth by using the tetracycline-
regulatable system. All mutants developed hallmarks of BAVMs, including cerebral …
Brain arteriovenous malformations (BAVMs) can cause devastating stroke in young people and contribute to half of all hemorrhagic stroke in children. Unfortunately, the pathogenesis of BAVMs is unknown. In this article we show that activation of Notch signaling in the endothelium during brain development causes BAVM in mice. We turned on constitutively active Notch4 (int3) expression in endothelial cells from birth by using the tetracycline-regulatable system. All mutants developed hallmarks of BAVMs, including cerebral arteriovenous shunting and vessel enlargement, by 3 weeks of age and died by 5 weeks of age. Twenty-five percent of the mutants showed signs of neurological dysfunction, including ataxia and seizure. Affected mice exhibited hemorrhage and neuronal cell death within the cerebral cortex and cerebellum. Strikingly, int3 repression resolved ataxia and reversed the disease progression, demonstrating that int3 is not only sufficient to induce, but also required to sustain the disease. We show that int3 expression results in widespread enlargement of the microvasculature, which coincided with a reduction in capillary density, linking vessel enlargement to Notch's known function of inhibiting vessel sprouting. Our data suggest that the Notch pathway is a molecular regulator of BAVM pathogenesis in mice, and offer hope that their regression might be possible by targeting the causal molecular lesion.
National Acad Sciences