Temporal and Spatial Regulation of Histone Deacetylase-7 and β-Catenin in Endothelial Cells

Abstract

See related article, pages 1202–1211 The importance of the endothelium to cardiovascular health cannot be overstated. This cell layer is the front line for regulation of vascular tone, permeability, platelet stability, and angiogenesis, with its dysfunction touted as a harbinger of cardiovascular disease.1–3 Turnover of the endothelium in adults is relatively low, but proliferation can be triggered by inflammation, matrix disruption, or ischemia.4 Our appreciation of this cell lining is acutely apparent following percutaneous coronary intervention, where delayed reendothelialization can cause thrombosis and exacerbate restenosis.5 An even greater challenge is the aging patient with eroding endothelial function.6 Indeed, an essential goal of cardiovascular science is to better elucidate the mechanisms that govern endothelial health and renewal. In this issue of Circulation Research , Margariti et al provide evidence for a relationship between β-catenin and histone deacetylase (HDAC)7 in human endothelial cells.7 Firstly, they demonstrate that overexpression of HDAC7 results in decreased β-catenin nuclear translocation, downregulation of β-catenin target genes, decreased β-catenin activity, and an associated inhibition of endothelial cell proliferation. Conversely, HDAC7 knockdown caused β-catenin nuclear translocation, but surprisingly also caused downregulation of cell cycle genes and a decrease in proliferation. These findings led Margariti et al to discover that HDAC7 can bind directly to β-catenin in endothelial cells. Moreover, vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation was shown to be associated with HDAC7 degradation, disruption of HDAC7–β-catenin binding and β-catenin nuclear translocation (Figure A). This novel protein–protein interaction balances nuclear trafficking and cytoplasmic sequestration of β-catenin, as well as transcriptional activity of β-catenin and degradation of HDAC7 (Figure, B). This intracellular trafficking impacts endothelial proliferation and sets the stage for novel feedback mechanisms in VEGF receptor signaling and VEGF transcription. Figure. HDAC7-β-catenin interactions in VEGF-stimulated endothelial cells. A , Summary of …