Histone deacetylase 7 maintains vascular integrity by repressing matrix metalloproteinase 10.
Development and homeostasis of the cardiovascular system require intimate interactions between endothelial and smooth muscle cells, which form a seamless circulatory network. We show that histone deacetylase 7 (HDAC7) is specifically expressed in the vascular endothelium during early embryogenesis, where it maintains vascular integrity by repressing the expression of matrix metalloproteinase (MMP) 10, a secreted endoproteinase that degrades the extracellular matrix. Disruption of the HDAC7 gene in mice results in embryonic lethality due to a failure in endothelial cell-cell adhesion and consequent dilatation and rupture of blood vessels. HDAC7 represses MMP10 gene transcription by associating with myocyte enhancer factor-2 (MEF2), a direct activator of MMP10 transcription and essential regulator of blood vessel development. These findings reveal an unexpected and specific role for HDAC7 in the maintenance of vascular integrity and have important implications for understanding the processes of angiogenesis and vascular remodeling during cardiovascular development and disease.
Chang
Shurong
S
Department of Molecular Biology, The University of Texas Southwestern Medical Center at Dallas, TX 75390, USA.
Young
Bryan D
BD
Li
Shijie
S
Qi
Xiaoxia
X
Richardson
James A
JA
Olson
Eric N
EN
D000818:Animals; D001011:Aorta / Q000166:cytology; D001808:Blood Vessels / Q000002:abnormalities; D018929:Cell Culture Techniques; D002460:Cell Line; D002678:Chimera / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000196:embryology / Q000201:enzymology* / Q000378:metabolism* / Q000648:ultrastructure; D005109:Extracellular Matrix / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D015971:Gene Expression Regulation, Enzymologic; D017930:Genes, Reporter; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D053506:Matrix Metalloproteinase 10; D008666:Metalloendopeptidases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D034622:RNA Interference; D013234:Stem Cells / Q000378:metabolism; D014471:Umbilical Veins / Q000166:cytology
D008156:Luciferases; D008666:Metalloendopeptidases; D053506:Matrix Metalloproteinase 10; C543273:HDAC7 protein, human; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases