Antiangiogenic therapy for portal hypertension in liver cirrhosis: Current progress and perspectives

Table 1 Drugs that can inhibit intrahepatic angiogenesis in portal hypertension

Ref.	Drugs	Experimental models	Effects
Liu et al[15], Qu et al[16], Wang et al[17], Thabut et al[18], Mejias et al[19]	Sorafenib	Biliary cirrhosis, non-alcoholic steatohepatitis, thioacetamide-, diethylnitrosamine-, dimethylnitrosamine-, and CCl4-induced cirrhosis	Suppresses the Raf/MEK/ERK signaling pathway and blocks the signaling from the VEGFR, PDGFR, and SCFR; therefore, increases apoptosis and decreases inflammation, fibrogenesis, angiogenesis, and hepatic vascular resistance
Tugues et al[20], Majumder et al[21]	Sunitinib	CCl4-induced cirrhosis and cell cultures (immortalized human activated HSC cell line, human HSC, and isolated primary human liver sinusoidal endothelial cells)	Blocks VEGFR1/2/3, PDGFR-α/β, FGFR, and SCFR; reduces HSC collagen synthesis, contractility, cellular migration, and SEC angiogenic capacity
Lin et al[22], Yang et al[23]	Brivanib	Biliary cirrhosis, non-alcoholic steatohepatitis	Inhibits VEGFR and FGFR; therefore, suppresses intrahepatic angiogenesis and portal hypertension, improves blood circulation, and hinders ascites formation
Miao et al[31], Marrone et al[32]	Simvastatin	CCl4-induced cirrhosis and LX-2 cell line	Enhances KLF2, through which deactivates SEC and reduces the severity of fibrosis and associated angiogenesis
Zhu et al[35]	Rifaximin	Biliary cirrhosis	Downregulates bacterial lipopolysaccharide binding to TLR4; therefore, reduces the severity of fibrosis and associated angiogenesis
Liu et al[37], Liu et al[38]	Largazole	Human colorectal carcinoma cells (HCT116, HT29, and HCT15), human HSC, and CCl4-induced cirrhosis	Suppresses the effects of CD34, VEGF, TGF-β1, and VEGFR2, blocking the main fibrogenic and angiogenic pathways
Michaelis et al[40]	Ribavirin	Human umbilical vein endothelial cells	Hinders angiogenesis by inhibiting inosine-5'-monophosphate dehydrogenase 1, tetrahydrobiopterin, NO, and cGMP

CCl₄: Carbon tetrachloride; VEGFR: Vascular endothelial growth factor receptor; PDGFR: Platelet-derived growth factor receptor; SCFR: Stem cell growth factor receptor; FGFR: Fibroblast growth factor receptor; HSC: Hepatic stellate cells; SEC: Sinusoidal endothelial cells; KLF2: Krüppel-like factor 2; TLR4: Toll-like receptor 4; TGF-β1: Transforming growth factor beta 1; NO: Nitric oxide; cGMP: Cyclic guanosine monophosphate.