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Project B02

Hepatic angiodiversity: Vascular control of liver function and disease

Microvascular endothelial cells (EC) act as organ-specific gatekeepers of their microenvironment to control organ function in health and disease. Liver sinusoidal EC (LSEC) are a prime model of angiodiversity. LSEC show unique molecular, phenotypic, and functional features and instruct the hepatic vascular niche by cellular interactions and angiokines. LSEC are discontinuous EC and guarantee high permeability across the sinusoidal wall by exhibiting fenestrations and absence of a basement membrane. Pathological changes of these highly specialized EC contribute to severe liver diseases ranging from alcoholic and non-alcoholic steatohepatitis to liver cirrhosis and from hepatocarcinogenesis to liver metastasis. During these disease processes, LSEC trans-differentiate towards a capillary phenotype (sinusoidal capillarization) aggravating disease progression. 
In the first funding period, we discovered that deficiency of the transcription factor GATA4 in adult LSEC caused sinusoidal capillarization, perisinusoidal liver fibrosis, hepatopathy, and impaired liver regeneration. Sinusoidal capillarization was accompanied by activation of Myc and by a pro-fibrotic angiocrine switch with de novo endothelial expression of hepatic stellate cell-activating cytokine PDGFB. In addition, we demonstrated that balanced angiocrine and autocrine Wnt signaling in sinusoidal EC are important not only for metabolic liver zonation, but also for maintaining LSEC differentiation, normal lipid metabolism, and erythropoiesis. Similar to Gata4, Alk1 signaling turned out to be upstream of Wnt signaling in LSEC indicating crosstalk between these two major LSEC regulatory pathways. 
In the second funding period, the major aim is to comprehensively study the vascular pathomechanisms that control liver fibrosis. Altogether, the final goal of this project is to identify cellular and molecular targets for prevention and treatment of liver disease.

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