Abstract 15236: The Histone Demethylase Jumonji D3 Regulates Angiogenesis
Vascular development is tightly controlled by epigenetic regulators. Histone modifications control specific gene expression, whereby trimethylation of histone H3 at lysine 27 (H3K27me3) represses expression. H3K27me3 can be erased e.g. by the demethylase Jumonji D3 (Jmjd3) to activate expression of target genes. The role of Jmjd3 in the regulation of vascular differentiation and angiogenesis is unclear. Using Jmjd3-depleted mouse embryonic stem cells, we demonstrate that Jmjd3 is required for mesoderm differentiation and vascular lineage commitment in vitro. Jmjd3 reduces H3K27me3 marks at the promoter of the mesoderm gene brachyury and facilitates recruitment of beta-catenin, which is critical for canonical Wnt signal-induced mesoderm differentiation. To investigate the importance of Jmjd3 function in endothelial cells (EC) in vivo, we generated global and EC-specific Jmjd3 knockout mice. Overall deletion of Jmjd3 is reflected in early embryonic lethality before E6.5 (n=17). In contrast, Tie2-Cre-specific knock out mice are viable but exhibit delayed postnatal angiogenesis in the retina (n=8), assessed by measuring vessel outgrowth (-15±6% vs. control, p<0.05), density (-17±3% vs. control, p<0.01 ) and branching (-18±5% vs. control, p<0.01). This inhibition of angiogenesis was mainly mediated by reduced EC proliferation (-32±9% vs. control, p<0.02) since only limited effects on sprout formation (-17±6% vs. control, p<0.03) and no effects on vessel regression were observed. In addition to delayed perinatal vascular outgrowth, EC-specific Jmjd3 is also required for ischemia-induced neovascularization (capillary density: -35±9% vs. control, p<0.01). Lack of Jmjd3 inhibits vessel perfusion (-87±8% vs. control, p<0.04) and increases necrosis after hind limb ischemia (n=4). Together, our study shows that EC-specific Jmjd3 ablation leads to impaired postnatal angiogenesis and reduced pathophysiological neovascularization after ischemia. Indeed, Wnt-reporter mice showed that Jmjd3 deletion reduces canonical Wnt signaling in the retina. Further studies determine whether the impaired EC function and disturbed endothelial Wnt signaling is caused by a demethylase-dependent epigenetic activity of Jmjd3.
Author Disclosures: T. Lucas: None. C. Zhao: None. K. Ohtani: None. A. Fischer: None. A.M. Zeiher: None. S. Dimmeler: None.
- © 2014 by American Heart Association, Inc.