Research progress on signaling pathways in cirrhotic portal hypertension

Figure 2 Proposed signaling pathways in the development of hepatic portal hypertension. RhoA/Rho-kinase: GGPP “lipidizes” RhoA to form membrane-bound RhoA and to activate Rho-kinase. AT1R stimulates JAK2 to phosphorylate and then activate Rho-kinase. Activated Rho-kinase phosphorylates the myosin targeting subunit 1, which inactivates myosin phosphatase. The inactivation of myosin phosphatase increases the phosphorylation of myosin light chain and promotes vasoconstriction. CPI-17 combines with myosin light chain phosphatase to inhibit the activation of the enzymes and promote the contraction of smooth muscle cells. The activation of Rho-kinase could downregulate the expression of eNOS and reduce its activity. The coupling of AT1R to Gaq/11 and Ga12/13 promotes Rho-kinase activation, which is involved in extracellular matrix production. JAK2/STAT3: Cytokines activate the JAK2/STAT3 pathway. Enhanced JAK2/STAT3 signaling upregulates TGF-β and iNOS expression and accelerates intestinal inflammation, which aggravates endothelial dysfunction and angiogenesis. IL-6 binds to its receptor, activates JAK2, phosphorylates it, and then causes the phosphorylation of STAT3 in cells, thereby activating HSC and promoting hypoxia inducible factor expression. These events can upregulate the activation of IL-6 and reactivate the STAT3 pathway, which forms a loop, constantly activating HSC, causing vessel contraction, and ultimately increasing portal pressure. AT1R: Angiotensin-type II receptor 1; CPI-17: C-protein inhibitor protein; eNOS: Endothelial nitric oxide synthase; GGPP: Geranylgeranyl pyrophosphate; HIF: Hypoxia inducible factor; HSC: Hepatic stellate cell; IL-6: Interleukin-6; IL-6R: Interleukin-6 receptor; iNOS: Inducible nitric oxide synthase; JAK2: Janus kinase 2; MLCP: Myosin light chain phosphatase; MP: Myosin phosphatase; MYPT1: Myosin phosphatase target subunit 1; RhoA: Ras homolog gene family member A; STAT3: Signal transducers and activators of transcription; TGF-β: Transforming growth factor β; VEGF: Vascular endothelial growth factor.