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.
Highlights
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
Our results indicate that internal elastin lamina (IEL) elastin levels are abnormal in brain AVMs, and in extracranial AVMs
We examined a wide range of human extracranial vascular malformations involving lymphatic, venous and arterial vessels and demonstrate that Notch proteins are expressed in each type
Summary
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. The Notch signaling pathway is triggered by binding of Notch proteins to any of four activating ligands (Delta-like [Dll[1], Dll4], Jagged [Jag[1], Jag2]) which trigger transmembrane cleavage by a gamma-secretase complex, resulting in release of the Notch intracellular domain (NICD), which activates transcription of downstream target genes such as EphrinB213 This is of particular interest because a number of gamma secretase inhibitors (GSI) have undergone phase I and II clinical trials in adults with Alzheimer’s disease[14,15] and in children and adults with cancer and related disorders[16,17,18]. That these drugs have known dosing and acceptable safety profiles makes them good candidates for drug repurposing for patients with other disorders such as vascular malformations
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