HDAC6 and ERK/ADAM17 Regulate VEGF-Induced NOTCH Signaling in Lung Endothelial Cells

Angiogenesis plays a critical role in various physiological and pathological processes and is regulated by VEGF. Histone Deacetylase 6 (HDAC6) is a class IIB HDAC that regulates cytoplasmic signaling through deacetylation and is emerging as a target for modulating angiogenesis. We investigated the h...

Full description

Saved in:
Bibliographic Details
Published in:Cells (Basel, Switzerland) Switzerland), 2023-09, Vol.12 (18), p.2231
Main Authors: Xia, Sheng, Menden, Heather L, Mabry, Sherry M, Sampath, Venkatesh
Format: Article
Language:English
Subjects:
Acetylation
Angiogenesis
Angiogenesis inhibitors
Blood vessels
Cell activation
Cellular signal transduction
Cyclin-dependent kinases
Deacetylation
Endothelial cells
Endothelium
Enzymes
ERK
Extracellular signal-regulated kinase
Gene expression
Gene silencing
HDAC6
Health aspects
Histone deacetylase
Intracellular signalling
Kinases
Laboratory animals
Lungs
Neonates
Notch signaling
Phosphorylation
Protein expression
Proteins
SKIP
Transcription activation
Vascular endothelial growth factor
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Angiogenesis plays a critical role in various physiological and pathological processes and is regulated by VEGF. Histone Deacetylase 6 (HDAC6) is a class IIB HDAC that regulates cytoplasmic signaling through deacetylation and is emerging as a target for modulating angiogenesis. We investigated the hypothesis that VEGF-induced endothelial cell (EC) NOTCH signaling is regulated by HDAC6 through acetylation of NOTCH intracellular cytoplasmic domain (NICD). In pulmonary endothelial cells (EC), VEGF-induced activation of the NICD transcriptional response was regulated by ERK1/2 and ADAM 17 and required DLL4. While HDAC6 inhibition induced the acetylation of NICD and stabilized NICD, it repressed NICD-SNW1 binding required for the NOTCH transcriptional responses. In vitro experiments showed that HDAC6 inhibition inhibited lung EC angiogenesis, and neonatal mice treated with a systemic HDAC6 inhibitor had significantly altered angiogenesis and alveolarization. These findings shed light on the role of HDAC6 in modulating VEGF-induced angiogenesis through acetylation and repression of the transcriptional regulators, NICD and SNW1.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells12182231