Endothelial Notch signaling is upregulated in human brain arteriovenous malformations and a mouse model of the disease.
Brain arteriovenous malformations (BAVMs) can cause lethal hemorrhagic stroke and have no effective treatment. The cellular and molecular basis for this disease is largely unknown. We have previously shown that expression of constitutively-active Notch4 receptor in the endothelium elicits and maintains the hallmarks of BAVM in mice, thus establishing a mouse model of the disease. Our work suggested that Notch pathway could be a critical molecular mediator of BAVM pathogenesis. Here, we investigated the hypothesis that upregulated Notch activation contributes to the pathogenesis of human BAVM. We examined the expression of the canonical Notch downstream target Hes1 in the endothelium of human BAVMs by immunofluorescence, and showed increased levels relative to either autopsy or surgical biopsy controls. We then analyzed receptor activity using an antibody to the activated form of the Notch1 receptor, and found increased levels of activity. These findings suggest that Notch activation may promote the development and even maintenance of BAVM. We also detected increases in Hes1 and activated Notch1 expression in our mouse model of BAVM induced by constitutively active Notch4, demonstrating molecular similarity between the mouse model and the human disease. Our work suggests that activation of Notch signaling is an important molecular candidate in BAVM pathogenesis and further validates that our animal model provides a platform to study the progression as well as the regression of the disease.
Murphy
Patrick A
PA
Pacific Vascular Research Laboratory, Division of Vascular Surgery, Department of Surgery, University of California, San Francisco, CA, USA.
Lu
Gloria
G
Shiah
Steven
S
Bollen
Andrew W
AW
Wang
Rong A
RA
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D002538:Intracranial Arteriovenous Malformations / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000096:biosynthesis*; D000074562:Receptor, Notch4; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000072056:Transcription Factor HES-1; D015854:Up-Regulation
D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D011518:Proto-Oncogene Proteins; D051881:Receptor, Notch1; D000074562:Receptor, Notch4; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; C073572:Notch4 protein, mouse; C078493:HES1 protein, human