title: Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin.
abstract: Histone deacetylases (HDACs) deacetylate histones and non-histone proteins, thereby affecting protein activity and gene expression. The regulation and function of the cytoplasmic class IIb HDAC6 in endothelial cells (ECs) is largely unexplored. Here, we demonstrate that HDAC6 is upregulated by hypoxia and is essential for angiogenesis. Silencing of HDAC6 in ECs decreases sprouting and migration in vitro and formation of functional vascular networks in matrigel plugs in vivo. HDAC6 regulates zebrafish vessel formation, and HDAC6-deficient mice showed a reduced formation of perfused vessels in matrigel plugs. Consistently, overexpression of wild-type HDAC6 increases sprouting from spheroids. HDAC6 function requires the catalytic activity but is independent of ubiquitin binding and deacetylation of α-tubulin. Instead, we found that HDAC6 interacts with and deacetylates the actin-remodelling protein cortactin in ECs, which is essential for zebrafish vessel formation and which mediates the angiogenic effect of HDAC6. In summary, we show that HDAC6 is necessary for angiogenesis in vivo and in vitro, involving the interaction and deacetylation of cortactin that regulates EC migration and sprouting.
authors.affiliation: Institute for Cardiovascular Regeneration, Centre of Molecular Medicine, University of Frankfurt, Frankfurt, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Kaluza
authors.forename: Jens
authors.initials: J
authors.lastname: Kroll
authors.forename: Sabine
authors.initials: S
authors.lastname: Gesierich
authors.forename: Tso-Pang
authors.initials: TP
authors.lastname: Yao
authors.forename: Reinier A
authors.initials: RA
authors.lastname: Boon
authors.forename: Eduard
authors.initials: E
authors.lastname: Hergenreider
authors.forename: Marc
authors.initials: M
authors.lastname: Tjwa
authors.forename: Lothar
authors.initials: L
authors.lastname: Rössig
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Zeiher
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
authors.forename: Carmen
authors.initials: C
authors.lastname: Urbich
mesh_terms: D000107:Acetylation; D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000201:enzymology; D002465:Cell Movement; D002478:Cells, Cultured; D051356:Cortactin / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic; D014404:Tubulin / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D051356:Cortactin; D014404:Tubulin; D029961:Zebrafish Proteins; C568523:HDAC6 protein, zebrafish; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases