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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:1782.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

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

Chang Hoon Ha; Bong Sook Jhun; Hung-Ying Kao; Zheng-Gen Jin

From the Aab Cardiovascular Research Institute and Department of Medicine (C.H.H., B.S.J., Z.-G.J.), University of Rochester Medical Center, New York; and the Department of Biochemistry, School of Medicine (H.-Y.K.), Case Western Reserve University, Cleveland, Ohio.

Correspondence to Zheng-Gen Jin, The Aab Cardiovascular Research Institute/Department of Medicine, University of Rochester Medical Center, 601 Elmwood Avenue Box 679, Rochester, New York 14642. E-mail zheng-gen_jin{at}urmc.rochester.edu

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 C/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.

This study investigated the role of HDAC7 in VEGF signaling and angiogenesis. We found that VEGF stimulated PKD1-dependent HDAC7 phosphorylation and cytoplasmic accumulation in endothelial cells modulating expression of genes including MT1-MMP and MMP10. Furthermore, our results showed that PKD1-HDAC7 pathway regulates VEGF-induced endothelial cell migration, tube formation, and microvessel sprouting.

Key Words: VEGF • histone deacetylase 7 • protein kinase D • gene expression • endothelial cells • angiogenesis

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Arterioscler Thromb Vasc Biol 2008 28: 1689-1690. [Extract] [Full Text] [PDF]