PMC

Nitric oxide (NO) signaling in normal and injured livers. NO synthesis is triggered via a pathway involving phosphatidylinositol-3-OH kinase (PI-3-K) and the serine-threonine kinase, Akt. Akt phosphorylation, stimulated by factors such as shear stress and growth factors, leads to endothelial NO synthase (eNOS) phosphorylation and NO production. G protein receptor kinase 2 (GRK2) interacts with, and influences Akt phosphorylation, and thus regulates endothelial NO synthase (eNOS) phosphorylation and activity. In the injured liver, GRK2 expression is upregulated and dampens Akt signaling, in turn reducing eNOS phosphorylation and NO production. eNOS is subject to other post-translational effects in the injured liver. Reproduced from Nature Medicine 11(9):952–8; Figure 6.

Changes in the hepatic sinusoid in response to injury. (A) A simplified version of a portal tract (left), central vein (right), and hepatic sinusoidal morphology with associated cell types within the sinusoid. (B) The sinusoid in response to liver injury; the upper panel depicts a cross-sectional image, whereas the lower panel shows a 3-dimensional view. In the normal state (left), sinusoidal endothelial cells produce NO supporting a low resistance state. In response to liver injury, extensive changes occur in the sinusoid. Liver injury (right) leads to both morphological as well as molecular abnormalities in sinusoidal endothelial cells and stellate cells. For example, endothelial cells become defenestrated, develop a defect in NO production, and concurrently increase production of other proteins such as endothelin and fibronectin that can contribute to stellate cell activation. Upon their activation, stellate cells develop an enhanced contractile phenotype and produce increased extracellular matrix. A number of paracrine and autocrine interactions occur between sinusoidal endothelial cells and stellate cells with some of the putative molecules and their associated functions as shown (gray box). Abbreviations: HSC, hepatic stellate cells; LSEC, liver sinusoidal endothelial cell; PDGF, platelet-derived growth factor; TGFβ, transforming growth factor β ; NO, nitric oxide. Reproduced from Journal of Hepatology 61:912–24; .