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

Laboratory investigation

Jian Tu M.D., Ph.D.1, Yang Li Ph.D.1, Zhiqiang Hu M.D., Ph.D.2, and Zhongbin Chen Ph.D.3
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  • 1 Australian School of Advanced Medicine, Macquarie University, Sydney, New South Wales, Australia;
  • | 2 Department of Neurosurgery, the 9th Medical Clinical College of Beijing University; and
  • | 3 Department of Electromagnetic and Laser Biology, Beijing Institute of Radiation Medicine, Beijing, China
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Object

Notch signaling has been suggested to promote the development and maintenance of arteriovenous malformations (AVMs), but whether radiosurgery inhibits Notch signaling pathways in AVMs is unknown. The aim of this study was to examine molecular changes of Notch signaling pathways following radiosurgery and to explore mechanisms of radiosurgical obliteration of “nidus” vessels in a rat model of AVMs.

Methods

One hundred eleven rats received common carotid artery–to–external jugular vein anastomosis to form an arteriovenous fistula (AVF) model. Six weeks postoperatively, dilated small vessels and capillaries formed a nidus. The rats with AVFs received 25-Gy radiosurgery. The expression of Notch1 and Notch4 receptors and their ligands, Delta-like1 and Delta-like4, Jagged1, Notch downstream gene target HES1, and an apoptotic marker caspase-3 in nidus vessels in the AVF rats was examined immunohistochemically and was quantified using LAS-AF software at 7 time points over a period of 42 days postradiosurgery. The interaction events between Notch1 receptor and Jagged1, as well as Notch4 receptor and Jagged1, were quantified in nidus vessels in the AVF rats using proximity ligation assay at different time points over 42 days postradiosurgery.

Results

The expression of Notch1 and Notch4 receptors, Delta-like1, Delta-like4, Jagged1, and HES1 was observed in nidus vessels in the AVF rats pre- and postradiosurgery. Radiosurgery enhanced apoptotic activity (p < 0.05) and inhibited the expression of Notch1 and Notch4 receptors and Jagged1 in the endothelial cells of nidus vessels in the AVF rats at 1, 2, 3, 7, 21, 28, and 42 days postradiosurgery (p < 0.05). Radiosurgery suppressed the interaction events between Notch1 receptor and Jagged1 (p < 0.001) as well as Notch4 receptor and Jagged1 (p < 0.001) in the endothelial cells of nidus vessels in the AVF rats over a period of 42 days postradiosurgery. Radiosurgery induced thrombotic occlusion of nidus vessels in the AVF rats. There was a positive correlation between the percentage of fully obliterated nidus vessels and time after radiosurgery (r = 0.9324, p < 0.001).

Conclusions

Radiosurgery inhibits endothelial Notch1 and Notch4 signaling pathways in nidus vessels while inducing thrombotic occlusion of nidus vessels in a rat model of AVMs. The underlying mechanisms of radiosurgery-induced AVM shrinkage could be a combination of suppressing Notch receptor signaling in blood vessel endothelial cells, leading to a reduction in nidus vessel size and thrombotic occlusion of nidus vessels.

Abbreviations used in this paper:

AVF = arteriovenous fistula; AVM = arteriovenous malformation; BSA = bovine serum albumin; CCA = common carotid artery; EJV = external jugular vein; MTT = 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NICD = Notch intracellular domain; PLA = proximity ligation assay; RBP-J kappa = J-kappa recombination signal-binding protein; VEGFR = vascular endothelial growth factor receptor.

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