VEGF stimulates HDAC7 phosphorylation and cytoplasmic accumulation modulating matrix metalloproteinase expression and angiogenesis.
OBJECTIVE
Histone acetylation/deacetylation plays an important role in the control of gene expression, tissue growth, and development. In particular, histone deacetylases 7 (HDAC7), a member of class IIa HDACs, is crucial in maintaining vascular integrity. However, whether HDAC7 is involved in the processes of vascular endothelial signaling and angiogenesis remains unclear. Here, we investigated the role of HDAC7 in vascular endothelial growth factor (VEGF) signaling and angiogenesis.


RESULTS
We show for the first time that VEGF stimulated phosphorylation of HDAC7 at the sites of Ser178, Ser344, and Ser479 in a dose- and time-dependent manner, which leads to the cytoplasmic accumulation of HDAC7. Using pharmacological inhibitors, siRNA, and adenoviruses carrying dominant-negative mutants, we found that phospholipase Cgamma/protein kinase C/protein kinase D1 (PKD1)-dependent signal pathway mediated HDAC7 phosphorylation and cytoplasmic accumulation by VEGF. Infection of ECs with adenoviruses encoding a mutant of HDAC7 specifically deficient in PKD1-dependent phosphorylation inhibited VEGF-induced angiogenic gene expression, including matrix metalloproteinases MT1-matrix metalloproteinase (MMP) and MMP10. Moreover, HDAC7 and its targeting genes were involved in VEGF-stimulated endothelial cell migration, tube formation, and microvessel sprouting.


CONCLUSIONS
Our results demonstrate that VEGF stimulates PKD1-dependent HDAC7 phosphorylation and cytoplasmic accumulation in endothelial cells modulating gene expression and angiogenesis.
Ha
Chang Hoon
CH
Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester Medical Center, Rochester, New York 14642, USA.
Jhun
Bong Sook
BS
Kao
Hung-Ying
HY
Jin
Zheng-Gen
ZG
D000818:Animals; D002417:Cattle; D002465:Cell Movement; D002478:Cells, Cultured; D003593:Cytoplasm / Q000201:enzymology; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology*; D015971:Gene Expression Regulation, Enzymologic; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D064326:MEF2 Transcription Factors; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018006:Myogenic Regulatory Factors / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021381:Protein Transport; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012694:Serine; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D042461:Vascular Endothelial Growth Factor A; D012694:Serine; C089212:protein kinase D; D040301:Vascular Endothelial Growth Factor Receptor-2; D011493:Protein Kinase C; D051966:Phospholipase C gamma; D020782:Matrix Metalloproteinases; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; C543273:HDAC7 protein, human; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases