Histone Deacetylase 7 and Transcriptional Regulatory Networks of the Vascular Endothelium

Cells respond to stimuli in part through the modulation of gene expression. Signal transduction from the environment to the nucleus culminates in the activation of factors that modify chromatin structure to either facilitate or inhibit gene transcription. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) are two such classes of enzymes that regulate the epigenetic code. Their opposing actions – to activate transcription by histone acetylation and to inhibit transcription by deacetylation – are tightly regulated to coordinate the vast gene programs required for cellular growth and differentiation. The class II HDACs are restricted in their expression patterns, and each have unique developmental and physiological functions. The studies described here focus on HDAC7, a class II HDAC that is expressed in vascular endothelial cells and whose function is essential for the maintenance of vascular integrity during embryogenesis. Mice lacking HDAC7 die by e11.5 with complex cardiovascular malformations including endothelial, vascular smooth muscle, and myocardial defects. By generating HDAC7 conditional knockout mice, it was observed that all of these defects are recapitulated in mice bearing an endothelial-specific deletion of HDAC7, but no defects are observed upon deletion of HDAC7 in the other cell types that were affected in the HDAC7 nulls. This in vivo evidence demonstrated that HDAC7 acts cell autonomously to maintain normal vascular development, and lead to the identification of the genetic abnormalities and mechanism leading to cardiovascular failure in the HDAC7 knockout. Further, this work begins the investigation of HDAC7 in adult vascular physiology, the findings of which will reveal new mechanisms whereby the vasculature responds to stress signals or disease. To this end, methods have been developed for the deletion of HDAC7 in the adult mouse using an inducible cre recombinase system together with the HDAC7 conditional allele. Additionally, these studies present progress toward the identification of the enhancer elements driving the endothelial-specific expression pattern of HDAC7. Detailed characterization of this enhancer is likely to implicate new signaling pathways as being involved in the genetic regulation of vascular development and maintenance. Finally, this work investigates the role of microRNAmediated gene silencing in the vascular system by identifying microRNAs involved in MEF2-dependent signaling in endothelial cells.