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National Institute of Environmental Health Sciences

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Publication Detail

Title: Notch signaling pathway is a potential therapeutic target for extracranial vascular malformations.

Authors: Davis, Reema B; Pahl, Kristy; Datto, Nicholas C; Smith, Scott V; Shawber, Carrie; Caron, Kathleen M; Blatt, Julie

Published In Sci Rep, (2018 12 20)

Abstract: Notch expression has been shown to be aberrant in brain arteriovenous malformations (AVM), and targeting Notch has been suggested as an approach to their treatment. It is unclear whether extracranial vascular malformations follow the same patterning and Notch pathway defects. In this study, we examined human extracranial venous (VM) (n = 3), lymphatic (LM) (n = 10), and AV (n = 6) malformations, as well as sporadic brain AVMs (n = 3). In addition to showing that extracranial AVMs demonstrate interrupted elastin and that AVMs and LMs demonstrate abnormal α-smooth muscle actin just as brain AVMS do, our results demonstrate that NOTCH1, 2, 3 and 4 proteins are overexpressed to varying degrees in both the endothelial and mural lining of the malformed vessels in all types of malformations. We further show that two gamma secretase inhibitors (GSIs), DAPT (GSI-IX) and RO4929097, cause dose-dependent inhibition of Notch target gene expression (Hey1) and rate of migration of monolayer cultures of lymphatic endothelial cells (hLECs) and blood endothelial cells (HUVEC). GSIs also inhibit HUVEC network formation. hLECs are more sensitive to GSIs compared to HUVEC. GSIs have been found to be safe in clinical trials in patients with Alzheimer's disease or cancer. Our results provide further rationale to support testing of Notch inhibitors in patients with extracranial vascular malformations.

PubMed ID: 30573741 Exiting the NIEHS site

MeSH Terms: Angiogenesis Inhibitors/pharmacology; Angiogenesis Inhibitors/therapeutic use; Cell Survival/drug effects; Cell Survival/genetics; Cells, Cultured; Gene Expression Regulation/drug effects; Human Umbilical Vein Endothelial Cells/drug effects; Human Umbilical Vein Endothelial Cells/physiology; Humans; Infant, Newborn; Lymphatic Vessels/drug effects; Lymphatic Vessels/metabolism; Molecular Targeted Therapy*; Neovascularization, Physiologic/drug effects; Neovascularization, Physiologic/genetics; Receptors, Notch/antagonists & inhibitors; Receptors, Notch/physiology*; Signal Transduction/drug effects; Signal Transduction/genetics; Vascular Malformations/genetics*; Vascular Malformations/pathology; Vascular Malformations/therapy*

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