title: Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis.
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.
authors.affiliation: Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14586, USA.
authors.forename: Chang Hoon
authors.initials: CH
authors.lastname: Ha
authors.forename: Weiye
authors.initials: W
authors.lastname: Wang
authors.forename: Bong Sook
authors.initials: BS
authors.lastname: Jhun
authors.forename: Chelsea
authors.initials: C
authors.lastname: Wong
authors.forename: Angelika
authors.initials: A
authors.lastname: Hausser
authors.forename: Klaus
authors.initials: K
authors.lastname: Pfizenmaier
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Zheng-Gen
authors.initials: ZG
authors.lastname: Jin
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects*; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010768:Phosphoserine / Q000378:metabolism; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D010768:Phosphoserine; C089212:protein kinase D; D040301:Vascular Endothelial Growth Factor Receptor-2; D011493:Protein Kinase C; D051966:Phospholipase C gamma; D006655:Histone Deacetylases