Portal hypertension in patients with nonalcoholic fatty liver disease: Current knowledge and challenges

Figure 2 Development of endothelial dysfunction and capillarization. A: The initial step in the development of endothelial dysfunction is the reduced production of nitric oxide (NO) caused by decreased endothelial nitric-oxide synthase (eNOS) activity and the low response of liver sinusoidal endothelial cells (LSECs) to acetylcholine; B: Reduced NO bioavailability can be caused by insulin resistance, heightened intracellular levels of reactive oxygen species and the formation of eNOS, paracrine and competitive inhibitors such as asymmetric dimethylarginine; C: Low levels of NO paired with increased endothelin 1 (ET-1) synthesis lead to sinusoidal contraction through the activation of perisinusoidal hepatic stellate cells (HSCs), resulting in elevated intrahepatic vascular resistance and the elevation of portal pressure; D: As a response to shear stress, hypoxia and inflammation, lipid-laden hepatocytes, cholangiocytes, LSECs, activated HSCs and Kupffer cells stimulate angiogenesis by producing an excessive amount of vascular endothelial growth factor (VEGF); E: Hypoxia in fatty liver is induced by mechanical pressure on sinusoids and increased lipid metabolism. Elevated VEGF concentrations lead to the promotion of angiogenesis and fibrogenesis by the increased fibrogenic functions of HSC, as well as LSEC capillarization and the secretion of hepatocyte growth factor. Capillarization, marked by the formation of the basal membrane and loss of fenestration, occurs as a result of LSECs exposure to lipid accumulation in parenchymal cells and a great amount of circulating lipids in the blood; F: As a response to excessive lipid exposure, LSECs express lipid-induced adhesion molecules (VCAM-1, VAP-1, etc.), activate Kupffer cells through the secretion of pro-inflammatory cytokines and induce leukocyte recruitment and their translocation into the liver parenchyma; G: Capillarized LSECs also activate HSCs through the release of angiocrine signals such as VEGF, transforming growth factor and hedgehog signals. Activated HSCs begin to deposit extracellular matrix, which increases tissue stiffness, further stimulating HSC activation; H: Shear stress downregulates the expression of ET-1 via Krüppel-like factors 2 (KLF2) activation. LSECs overexpress KLF2 to maintain HSCs in a quiescent state as a compensatory mechanism to manage vascular dysfunction. Unfortunately, this is an insufficient mechanism for preventing portal hypertension development. ACh: Acetylcholine; aHSC: Activated hepatic stellate cell; KC: Kupffer cell; ROS: Reactive oxygen species; HIF: Hypoxia-inducible factor; M-CSF: Macrophage colony-stimulating factor; MCP1: Monocyte chemoattractant protein-1; IR: Insulin resistance; ADMA: Asymmetric dimethylarginine; HGF: Hepatocyte growth factor; VCAM-1: Vascular cell adhesion molecule 1; VAP-1: Vascular adhesion protein-1; IL-1: Interleukin-1; IL-6: Interleukin-6; TNFα: Tumor necrosis factor α; TGF-β: Transforming growth factor; Hh: Hedgehog signals.