Abstract
Maintenance of vascular integrity is required for embryogenesis and organ homeostasis. However, the gene expression programs that stabilize blood vessels are poorly understood. Here, we show that the histone methyltransferase Ezh2 maintains integrity of the developing vasculature by repressing a transcriptional program that activates expression of Mmp9. Inactivation of Ezh2 in developing mouse endothelium caused embryonic lethality with compromised vascular integrity and increased extracellular matrix degradation. Genome-wide approaches showed that Ezh2 targets Mmp9 and its activators Fosl1 and Klf5. In addition, we uncovered Creb3l1 as an Ezh2 target that directly activates Mmp9 gene expression in the endothelium. Furthermore, genetic inactivation of Mmp9 rescued vascular integrity defects in Ezh2-deficient embryos. Thus, epigenetic repression of Creb3l1, Fosl1, Klf5 and Mmp9 by Ezh2 in endothelial cells maintains the integrity of the developing vasculature, potentially linking this transcriptional network to diseases with compromised vascular integrity.
Highlights
Stability of the vasculature is essential for embryonic development and tissue homeostasis
We addressed the ability of Creb3l1, FOS-like antigen 1 (Fosl1), Kruppel-like factor 5 (Klf5) and CCAAT/enhancer-binding protein ε (Cebpe) to activate Mmp9 gene expression in endothelial cells. cDNAs encoding these transcription factors were overexpressed in bovine aortic endothelial cells (BAECs), in which we measured endogenous Mmp9 by quantitative PCR (qPCR) and protein levels by western blot
We found that Ezh2 stabilizes the developing vasculature by repressing a transcriptional pathway that activates Mmp9 (Fig. 4F)
Summary
Stability of the vasculature is essential for embryonic development and tissue homeostasis. Endothelial extracellular matrix (ECM) homeostasis is key for vascular stability during development (Ingram et al, 2013), as the ECM provides a scaffold that supports the organization of endothelial cells into blood vessels (Davis and Senger, 2005), and its degradation by increased activity of matrix. MMP9 expression must be kept in check to maintain vascular integrity
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