Hepatic microcirculation and mechanisms of portal hypertension

The liver microcirculatory milieu, mainly composed of liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs) and hepatic macrophages, has an essential role in liver homeostasis, including in preserving hepatocyte function, regulating the vascular tone and controlling inflammation. Liver microcirculatory dysfunction is one of the key mechanisms that promotes the progression of chronic liver disease (also termed cirrhosis) and the development of its major clinical complication, portal hypertension. In the present Review, we describe the current knowledge of liver microcirculatory dysfunction in cirrhotic portal hypertension and appraise the preclinical models used to study the liver circulation. We also provide a comprehensive summary of the promising therapeutic options to target the liver microvasculature in cirrhosis. Liver microcirculatory dysfunction is one of the key mechanisms that promotes the progression of chronic liver disease. In this Review, the authors explore the role of liver microcirculatory dysfunction in cirrhotic portal hypertension, the preclinical models used to study liver circulation and potential therapeutics. Key points Portal hypertension is the most important non-neoplastic complication of chronic liver disease, leading to high morbidity and mortality. A pathological increase in intrahepatic vascular resistance, which derives from profound deregulation in the phenotype of all hepatic cell types, is the primary factor in the development of portal hypertension. Mechanisms leading to increased intrahepatic vascular resistance in cirrhosis are thought to include overactivation of vasoconstrictor pathways and downregulation of vasodilator signalling in the sinusoidal milieu. Treatments targeting intrahepatic vascular resistance developed in preclinical models have exhibited very low success at the bedside, encouraging further research and the development of new models. Current methods to understand the pathophysiology of portal hypertension and develop new therapeutics include preclinical animals models, conventional in vitro approaches and new in vitro methods that combine biological scaffolds with primary cells. Improved characterization of portal hypertension pathophysiology and discovery of new therapeutic targets need to be done using preclinical models that mimic the clinical scenario and consider the current epidemiology of the disease.