Protein Kinase D-dependent Phosphorylation and Nuclear Export of Histone Deacetylase 5 Mediates Vascular Endothelial Growth Factor-induced Gene Expression and Angiogenesis

Angelika Hausser,Chang Hoon Ha,Timothy A Mckinsey,Weiye Wang,Zheng-Gen Jin,Chelsea Wong,Eric N Olson,Klaus Pfizenmaier,Bong Sook Jhun

doi:10.1074/jbc.m800264200

Abstract

Vascular endothelial growth factor (VEGF) is essential for normal and pathological angiogenesis. However, the signaling pathways linked to gene regulation in VEGF-induced angiogenesis are not fully understood. Here we demonstrate a critical role of protein kinase D (PKD) and histone deacetylase 5 (HDAC5) in VEGF-induced gene expression and angiogenesis. We found that VEGF stimulated HDAC5 phosphorylation and nuclear export in endothelial cells through a VEGF receptor 2-phospholipase Cgamma-protein kinase C-PKD-dependent pathway. We further showed that the PKD-HDAC5 pathway mediated myocyte enhancer factor-2 transcriptional activation and a specific subset of gene expression in response to VEGF, including NR4A1, an orphan nuclear receptor involved in angiogenesis. Specifically, inhibition of PKD by overexpression of the PKD kinase-negative mutant prevents VEGF-induced HDAC5 phosphorylation and nuclear export as well as NR4A1 induction. Moreover, a mutant of HDAC5 specifically deficient in PKD-dependent phosphorylation inhibited VEGF-mediated NR4A1 expression, endothelial cell migration, and in vitro angiogenesis. These findings suggest that the PKD-HDAC5 pathway plays an important role in VEGF regulation of gene transcription and angiogenesis.

Highlights

Angiogenesis, the formation of new blood capillaries, is an important component of embryonic vascular development, wound healing, and organ regeneration, as well as the pathological processes such as diabetic retinopathies, atherosclerosis, and tumor growth [1,2,3]
We found that Vascular endothelial growth factor (VEGF) stimulated histone deacetylase 5 (HDAC5) phosphorylation and nuclear export in endothelial cells through a VEGF receptor 2-phospholipase C␥-protein kinase C-Protein kinase D (PKD)-dependent pathway
We further showed that the PKD-HDAC5 pathway mediated myocyte enhancer factor-2 transcriptional activation and a specific subset of gene expression in response to VEGF, including NR4A1, an orphan nuclear receptor involved in angiogenesis

Summary

Introduction

Angiogenesis, the formation of new blood capillaries, is an important component of embryonic vascular development, wound healing, and organ regeneration, as well as the pathological processes such as diabetic retinopathies, atherosclerosis, and tumor growth [1,2,3]. We found that VEGF stimulated HDAC5 phosphorylation and nuclear export in endothelial cells through a VEGF receptor 2-phospholipase C␥-protein kinase C-PKD-dependent pathway. We further showed that the PKD-HDAC5 pathway mediated myocyte enhancer factor-2 transcriptional activation and a specific subset of gene expression in response to VEGF, including NR4A1, an orphan nuclear receptor involved in angiogenesis.

Results

Conclusion