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Brain Advance Access published online on October 7, 2009
Brain, doi:10.1093/brain/awp246
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© The Author (2009). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Qichuan ZhuGe1,*, Ming Zhong1,*, WeiMing Zheng1, Guo-Yuan Yang2,3, XiaoOu Mao4, Lin Xie4, Gourong Chen5, Yongmei Chen2, Michael T. Lawton3, William L. Young2,3,6, David A. Greenberg4 and Kunlin Jin1,4

1 Department of Neurosurgery, First Affiliated Hospital, Wenzhou Medical College, Wenzhou, China 2 Department of Anesthesia and Perioperative Care, Center for Cerebrovascular Research, University of California, San Francisco, CA 94121, USA 3 Department of Neurological Surgery, University of California, San Francisco, CA 94121, USA 4 Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA 5 Department of Pathology, First Affiliated Hospital, Wenzhou Medical College, Wenzhou, China 6 Department of Neurology, University of California, San Francisco, CA 94121, USA

Correspondence to: Kunlin Jin, MD, PhD, Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA E-mail: kjin{at}buckinstitute.org

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.

Key Words: Notch-1; AVM; human; brain; signalling; angiogenesis

Abbreviations: AVM, arteriovenous malformations; Dll4, anti-Delta-like-4; NICD, intracellular domain of Notch; TGF, tumour growth factor

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Received January 15, 2009. Revised July 28, 2009. Accepted August 21, 2009.

*These authors contributed equally to this work.


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