Liver sinusoidal endothelial cells control liver development and function

Microvascular endothelial cells (ECs) are increasingly recognized as organ-specific gatekeepers of their microenvironment. Liver sinusoidal endothelial cells (LSECs) are characterized by many fenestrae with uniform diameters of 100-150 nm, thus creating open channels for the exchange of substances between the blood and liver parenchyma. The transcription factor GATA4 acts as a master regulator of hepatic microvascular specification and acquisition of organ-specific vascular competence, indispensable for liver development. GATA4 was shown to have a role in LSEC specification and function. The specific deletion of GATA4 in LSEC caused the transformation of discontinuous liver sinusoids into continuous capillaries. Capillarization process was characterized by basement membrane deposition and formation of a continuous EC layer. The switch from discontinuous LSECs to continuous ECs during embryogenesis caused embryonic lethality due to liver hypoplasia, fibrosis, and impaired colonization by hematopoietic progenitor cells, resulting in anemia. Genetic deletion of the transcription factor GATA4 in LSECs was found to cause liver fibrosis and impairs liver regeneration. The role of GATA4 in LSECs was investigated as potential therapeutic targets for this liver fibrosis. Liver fibrosis is characterized by the activation of Hepatic stellate cells (HSC). GATA4 demonstrated to have a role in the deactivation of active hepatic stellate cells, inducing a regression of liver fibrosis. The lack of GATA4 in adult mice LSECs caused hepatic stellate cell activation and, consequently, liver fibrosis. Studies demonstrated that during regression of liver fibrosis Gata4 was re-expressed in deactivated HSCs. Further investigations showed that the overexpression of Gata4 in HSCs promoted liver fibrosis regression in Carbon tetrachloride (CCl4) -treated mice. In this studies GATA4-overexpression induced changes in the expression of fibrogenic and antifibrogenic genes, promoting hepatic stellate cell deactivation. Specifically, GATA4 directly repressed endothelial PAS 1 (EPAS1) transcription in HSC. In conclusion, it can be said that GATA4 may represent a potential therapeutic approach for liver fibrosis.