TY  - JOUR
AU  - Géraud, Cyrill
AU  - Koch, Philipp-Sebastian
AU  - Zierow, Johanna
AU  - Klapproth, Kay
AU  - Busch, Katrin
AU  - Olsavszky, Victor
AU  - Leibing, Thomas
AU  - Demory, Alexandra
AU  - Ulbrich, Friederike
AU  - Diett, Miriam
AU  - Singh, Sandhya
AU  - Sticht, Carsten
AU  - Breitkopf-Heinlein, Katja
AU  - Richter, Karsten
AU  - Karppinen, Sanna-Maria
AU  - Pihlajaniemi, Taina
AU  - Arnold, Bernd
AU  - Rodewald, Hans-Reimer
AU  - Augustin, Hellmut
AU  - Schledzewski, Kai
AU  - Goerdt, Sergij
TI  - GATA4-dependent organ-specific endothelial differentiation controls liver development and embryonic hematopoiesis.
JO  - The journal of clinical investigation
VL  - 127
IS  - 3
SN  - 1558-8238
CY  - Ann Arbor, Mich.
PB  - ASCJ
M1  - DKFZ-2017-00797
SP  - 1099 - 1114
PY  - 2017
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:28218627
C2  - pmc:PMC5330741
DO  - DOI:10.1172/JCI90086
UR  - https://inrepo02.dkfz.de/record/120363
ER  -