title: The NuRD chromatin-remodeling enzyme CHD4 promotes embryonic vascular integrity by transcriptionally regulating extracellular matrix proteolysis.
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.
authors.affiliation: Cardiovascular Biology Research Program; Oklahoma Medical Research Foundation; Oklahoma City, Oklahoma, United States of America ; Department of Cell Biology; University of Oklahoma Health Sciences Center; Oklahoma City, Oklahoma, United States of America.
authors.forename: Kyle G
authors.initials: KG
authors.lastname: Ingram
authors.affiliation: Cardiovascular Biology Research Program; Oklahoma Medical Research Foundation; Oklahoma City, Oklahoma, United States of America.
authors.forename: Carol D
authors.initials: CD
authors.lastname: Curtis
authors.affiliation: Cardiovascular Biology Research Program; Oklahoma Medical Research Foundation; Oklahoma City, Oklahoma, United States of America.
authors.forename: Robert
authors.initials: R
authors.lastname: Silasi-Mansat
authors.affiliation: Cardiovascular Biology Research Program; Oklahoma Medical Research Foundation; Oklahoma City, Oklahoma, United States of America ; Department of Cell Biology; University of Oklahoma Health Sciences Center; Oklahoma City, Oklahoma, United States of America ; Department of Pathology; University of Oklahoma Health Sciences Center; Oklahoma City, Oklahoma, United States of America.
authors.forename: Florea
authors.initials: F
authors.lastname: Lupu
authors.affiliation: Cardiovascular Biology Research Program; Oklahoma Medical Research Foundation; Oklahoma City, Oklahoma, United States of America ; Department of Cell Biology; University of Oklahoma Health Sciences Center; Oklahoma City, Oklahoma, United States of America.
authors.forename: Courtney T
authors.initials: CT
authors.lastname: Griffin
mesh_terms: D000818:Animals; D001808:Blood Vessels / Q000254:growth & development / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D004265:DNA Helicases / Q000096:biosynthesis / Q000235:genetics*; D005109:Extracellular Matrix / Q000235:genetics* / Q000378:metabolism; D005341:Fibrinolysin / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics*; D059748:Proteolysis; D055293:Receptors, Urokinase Plasminogen Activator / Q000096:biosynthesis; D019700:Thrombospondin 1 / Q000096:biosynthesis; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator; D019700:Thrombospondin 1; C585483:Thbs1 protein, mouse; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; C509277:Mi-2beta protein, mouse; D004265:DNA Helicases