title: GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis.
abstract: Microvascular endothelial cells (ECs) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Microvascular ECs instruct neighboring cells in their organ-specific vascular niches through angiocrine factors, which include secreted growth factors (angiokines), extracellular matrix molecules, and transmembrane proteins. However, the molecular regulators that drive organ-specific microvascular transcriptional programs and thereby regulate angiodiversity are largely elusive. In contrast to other ECs, which form a continuous cell layer, liver sinusoidal ECs (LSECs) constitute discontinuous, permeable microvessels. Here, we have shown that the transcription factor GATA4 controls murine LSEC specification and function. LSEC-restricted deletion of Gata4 caused transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization was characterized by ectopic basement membrane deposition, formation of a continuous EC layer, and increased expression of VE-cadherin. Correspondingly, ectopic expression of GATA4 in cultured continuous ECs mediated the downregulation of continuous EC-associated transcripts and upregulation of LSEC-associated genes. The switch from discontinuous LSECs to continuous ECs during embryogenesis caused liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells, resulting in anemia and embryonic lethality. Thus, GATA4 acts as master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence, which are indispensable for liver development. The data also establish an essential role of the hepatic microvasculature in embryonic hematopoiesis.
authors.forename: Cyrill
authors.initials: C
authors.lastname: Géraud
authors.forename: Philipp-Sebastian
authors.initials: PS
authors.lastname: Koch
authors.forename: Johanna
authors.initials: J
authors.lastname: Zierow
authors.forename: Kay
authors.initials: K
authors.lastname: Klapproth
authors.forename: Katrin
authors.initials: K
authors.lastname: Busch
authors.forename: Victor
authors.initials: V
authors.lastname: Olsavszky
authors.forename: Thomas
authors.initials: T
authors.lastname: Leibing
authors.forename: Alexandra
authors.initials: A
authors.lastname: Demory
authors.forename: Friederike
authors.initials: F
authors.lastname: Ulbrich
authors.forename: Miriam
authors.initials: M
authors.lastname: Diett
authors.forename: Sandhya
authors.initials: S
authors.lastname: Singh
authors.forename: Carsten
authors.initials: C
authors.lastname: Sticht
authors.forename: Katja
authors.initials: K
authors.lastname: Breitkopf-Heinlein
authors.forename: Karsten
authors.initials: K
authors.lastname: Richter
authors.forename: Sanna-Maria
authors.initials: SM
authors.lastname: Karppinen
authors.forename: Taina
authors.initials: T
authors.lastname: Pihlajaniemi
authors.forename: Bernd
authors.initials: B
authors.lastname: Arnold
authors.forename: Hans-Reimer
authors.initials: HR
authors.lastname: Rodewald
authors.forename: Hellmut G
authors.initials: HG
authors.lastname: Augustin
authors.forename: Kai
authors.initials: K
authors.lastname: Schledzewski
authors.forename: Sergij
authors.initials: S
authors.lastname: Goerdt
mesh_terms: D000818:Animals; D002196:Capillaries / Q000196:embryology; D002454:Cell Differentiation / Q000502:physiology*; D004622:Embryo, Mammalian / Q000201:enzymology*; D042783:Endothelial Cells / Q000378:metabolism*; D004727:Endothelium / Q000196:embryology*; D050991:GATA4 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D006410:Hematopoiesis / Q000502:physiology*; D008099:Liver / Q000098:blood supply / Q000196:embryology*; D051379:Mice; D008822:Mice, Transgenic; D009928:Organ Specificity / Q000502:physiology
chemical_list: D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse