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.

Table 2 Drugs that can inhibit extrahepatic angiogenesis in portal hypertension

Ref.	Drugs	Experimental models	Effects
Fernandez et al[46]	Rapamycin and glivec	Partial portal vein ligation	Downregulates VEGF, VEGFR2, CD31, PDGF, PDGFR-β, and α-SMA
Mejias et al[19]	Sorafenib	Partial portal vein ligation and CCl4-induced cirrhosis	Blocks VEGF, PDGF, and Raf/MEK/ERK signaling pathway; therefore, reduces intraorgan and systemic blood flow, splanchnic neovascularization, portosystemic shunting, hepatic vascular resistance, and portal pressure
Woltering et al[49], Mejias et al[50]	Somatostatin and its synthetic analogs	Partial portal vein ligation	Reduces VEGF and CD31 expression, splanchnic neovascularization, and portosystemic collateral circulation by blocking SSTR2
Miternique-Grosse et al[55]	Spironolactone	Biliary cirrhosis	Suppresses the effects of aldosterone and the VEGF signal transduction pathway
Lee et al[58]	N-acetylcysteine	Biliary cirrhosis	Reduces oxidative stress, inflammatory cytokine levels, TNF-α, VEGF, VEGFR2, Ang1, CD31 expression, and suppresses Akt/eNOS/NO pathway
Hsu et al[61]	Bosentan and ambrisentan	Biliary cirrhosis	Block endothelin receptors and suppress iNOS, cyclooxygenase 2, VEGF, VEGFR2, and Akt signaling
Schwabl et al[64]	Pioglitazone	Biliary cirrhosis	Downregulates inflammatory genes and NF-κB expression, suppresses angiogenic and pro-inflammatory cytokines, chemokines, and growth factors (VEGF, PDGF, and PIGF)
Li et al[66]	Thalidomide	Biliary cirrhosis	Hinders TNF-α/interleukin-1β production and blocks the TNFα-VEGF-NOS-NO pathway
Hsu et al[67]	Catechins of Camellia sinensis	Biliary cirrhosis	Reduce HIF-1α expression, Akt signaling, and VEGF synthesis
Hsin et al[68]	2’-hydroxyflavonoid	Thioacetamide-induced liver cirrhosis	Downregulates apoptosis
Hsu et al[69]	Curcumin	Biliary cirrhosis	Suppresses VEGF, cyclooxygenase 2, and eNOS

CCl₄: Carbon tetrachloride; VEGFR: Vascular endothelial growth factor receptor; PDGFR: Platelet-derived growth factor receptor; α-SMA: Alpha smooth muscle actin; SSTR2: Somatostatin receptor type 2; TNF-α: Tumor necrosis factor alpha; Ang1: Angiopoietin 1; eNOS: Endothelial nitric oxide synthase; NO: Nitric oxide; iNOS: Inducible nitric oxide synthase; NF-κB: Factor kappa-light-chain-enhancer of activated B cells; PIGF: Placental growth factor; HIF-1α: Hypoxia-inducible factor-1 alpha.