VEGF Stimulates HDAC7 Phosphorylation and Cytoplasmic Accumulation Modulating Matrix Metalloproteinase Expression and Angiogenesis

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 28; no. 10; pp. 1782 - 1788
• Main Authors: Ha, Chang Hoon, Jhun, Bong Sook, Kao, Hung-Ying, Jin, Zheng-Gen
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01.10.2008; Hagerstown, MD Lippincott
• Subjects: Animals; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cardiovascular system; Cattle; Cell Movement; Cells, Cultured; Cytoplasm - enzymology; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - drug effects; Endothelial Cells - enzymology; Gene Expression Regulation, Enzymologic; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Humans; Matrix Metalloproteinase 10 - metabolism; Matrix Metalloproteinase 14 - metabolism; Matrix Metalloproteinases - genetics; Matrix Metalloproteinases - metabolism; Medical sciences; MEF2 Transcription Factors; Mice; Myogenic Regulatory Factors - metabolism; Neovascularization, Physiologic - drug effects; Neovascularization, Physiologic - genetics; Pharmacology. Drug treatments; Phospholipase C gamma - metabolism; Phosphorylation; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein Kinase Inhibitors - pharmacology; Protein Transport; RNA Interference; RNA, Small Interfering - metabolism; Serine; Signal Transduction - drug effects; Signal Transduction - genetics; Time Factors; Transfection; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; Vasodilator agents. Cerebral vasodilators; Endothelial cell; Phosphorylation; endothelial cells; histone deacetylase 7; Enzyme; Transferases; Non-specific serine/threonine protein kinase; VEGF; Cardiovascular disease; Gene expression; Vascular disease; Angiogenesis; Atherosclerosis; protein kinase D
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.108.172528

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. METHODS AND 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 Cγ/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.