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Chronic liver disease leads to profound changes of the sinusoidal vascular network with development of portal hypertension. Microvasculature in cirrhotic liver is remodeled and abnormal with vessels of varying diameter separated into micronodules. Several processes have been recognized to lead to vascular remodeling in the liver: On a cellular level resting stellate cells become activated and start to deposit matrix proteins, which will lead to formation of a basement membrane around the sinusoids. Liver sinusoidal endothelial cells (LSEC) become dysfunctional and deficient for production i.e. of the vasodilator nitric oxide. These changes finally will transform the low resistance vascular bed leading to portal hypertension with all its consequences such as variceal bleeding, formation of collateral vessels porto-systemic shunts and formation of ascites. Although contractility of hepatic stellate cells and matrix deposition are well established in the process of cirrhosis and portal hypertension, the role of LSEC signaling and sinusoidal vascular remodeling are less understood. Under physiological conditions, LSEC are resting and highly differentiated cells showing unique morphology with fenestrations and a lack of a basement membrane. However, in chronic liver disease, LSEC become activated, start to proliferate, upregulate various arterial surface markers and loose their fenestrations eventually leading to dedifferentiation and capillarisation of the hepatic microvascular bed. A key signaling pathway in vascular differentiation and interendothelial cell interactions is Notch signaling. Notch signaling plays a pivotal role in embryonic vascular development and vascular differentiation. Notch-1 receptor and its ligands Jagged and DLL are expressed in healthy adult liver. However, their function in liver is unknown. We have discovered that Notch-1 knockout in mice rapidly leads to profound vascular remodeling and dysfunctional hepatic microcirculation with subsequent portal hypertension and nodular regenerative hyperplasia, a chronic liver disease characterized by transformation of liver parenchyma into regenerative nodules. The aim of this study is to elucidate the role of Notch-1 in LSEC and in chronic liver disease using an established murine model of liver fibrosis and portal hypertension as well as using liver biopsies from patients with chronic liver disease.