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@ARTICLE{Graud:120363,
author = {C. Géraud and P.-S. Koch and J. Zierow and K.
Klapproth$^*$ and K. Busch$^*$ and V. Olsavszky and T.
Leibing and A. Demory and F. Ulbrich and M. Diett and S.
Singh and C. Sticht and K. Breitkopf-Heinlein and K.
Richter$^*$ and S.-M. Karppinen and T. Pihlajaniemi and B.
Arnold$^*$ and H.-R. Rodewald$^*$ and H. Augustin$^*$ and K.
Schledzewski and S. Goerdt},
title = {{GATA}4-dependent organ-specific endothelial
differentiation controls liver development and embryonic
hematopoiesis.},
journal = {The journal of clinical investigation},
volume = {127},
number = {3},
issn = {1558-8238},
address = {Ann Arbor, Mich.},
publisher = {ASCJ},
reportid = {DKFZ-2017-00797},
pages = {1099 - 1114},
year = {2017},
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.},
cin = {D110 / A190 / W230 / D050},
ddc = {610},
cid = {I:(DE-He78)D110-20160331 / I:(DE-He78)A190-20160331 /
I:(DE-He78)W230-20160331 / I:(DE-He78)D050-20160331},
pnm = {321 - Basic Concepts (POF3-321)},
pid = {G:(DE-HGF)POF3-321},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:28218627},
pmc = {pmc:PMC5330741},
doi = {10.1172/JCI90086},
url = {https://inrepo02.dkfz.de/record/120363},
}