The NuRD chromatin-remodeling enzyme CHD4 promotes embryonic vascular integrity by transcriptionally regulating extracellular matrix proteolysis

PLoS Genet. 2013;9(12):e1004031. doi: 10.1371/journal.pgen.1004031. Epub 2013 Dec 12.

Abstract

The extracellular matrix (ECM) supports vascular integrity during embryonic development. Proteolytic degradation of ECM components is required for angiogenesis, but excessive ECM proteolysis causes blood vessel fragility and hemorrhage. Little is understood about how ECM proteolysis is transcriptionally regulated during embryonic vascular development. We now show that the NuRD ATP-dependent chromatin-remodeling complex promotes vascular integrity by preventing excessive ECM proteolysis in vivo. Mice lacking endothelial CHD4--a catalytic subunit of NuRD complexes--died at midgestation from vascular rupture. ECM components surrounding rupture-prone vessels in Chd4 mutants were significantly downregulated prior to embryonic lethality. Using qPCR arrays, we found two critical mediators of ECM stability misregulated in mutant endothelial cells: the urokinase-type plasminogen activator receptor (uPAR or Plaur) was upregulated, and thrombospondin-1 (Thbs1) was downregulated. Chromatin immunoprecipitation assays showed that CHD4-containing NuRD complexes directly bound the promoters of these genes in endothelial cells. uPAR and THBS1 respectively promote and inhibit activation of the potent ECM protease plasmin, and we detected increased plasmin activity around rupture-prone vessels in Chd4 mutants. We rescued ECM components and vascular rupture in Chd4 mutants by genetically reducing urokinase (uPA or Plau), which cooperates with uPAR to activate plasmin. Our findings provide a novel mechanism by which a chromatin-remodeling enzyme regulates ECM stability to maintain vascular integrity during embryonic development.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Vessels / growth & development
  • Blood Vessels / metabolism
  • Chromatin Assembly and Disassembly / genetics
  • DNA Helicases / biosynthesis
  • DNA Helicases / genetics*
  • Extracellular Matrix / genetics*
  • Extracellular Matrix / metabolism
  • Fibrinolysin / genetics
  • Gene Expression Regulation, Developmental
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex / genetics
  • Mice, Transgenic
  • Neovascularization, Physiologic / genetics*
  • Proteolysis*
  • Receptors, Urokinase Plasminogen Activator / biosynthesis
  • Thrombospondin 1 / biosynthesis
  • Urokinase-Type Plasminogen Activator / metabolism

Substances

  • Receptors, Urokinase Plasminogen Activator
  • Thrombospondin 1
  • thrombospondin-1, mouse
  • Fibrinolysin
  • Urokinase-Type Plasminogen Activator
  • Mi-2 Nucleosome Remodeling and Deacetylase Complex
  • Mi-2beta protein, mouse
  • DNA Helicases