Endothelin receptor blockers reduce shunting and angiogenesis in cirrhotic rats Shao-Jung Hsu *,†,‡ , Te-Yueh Lin § , Sun-Sang Wang *,¶ , Chiao-Lin Chuang *,§ , Fa-Yauh Lee *,‡ , Hui-Chun Huang *,‡,§ , I-Fang Hsin †,** , Jing-Yi Lee † , Han-Chieh Lin *,‡ and Shou-Dong Lee *,†† * Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan, † Institute of Pharmacology, National Yang-Ming University School of Medicine, Taipei, Taiwan, ‡ Division of Gastroenterologyand Hepatology, Taipei Veterans General Hospital, Taipei, Taiwan, § Division of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ¶ Department of Medical Affair and Planning, Taipei Veterans General Hospital, Taipei, Taiwan, ** Endoscopy Center for Diagnosis and Treatment, Taipei Veterans General Hospital, Taipei, Taiwan, †† Division of Gastroenterology, Department of Medicine, Cheng Hsin General Hospital, Taipei, Taiwan ABSTRACT Background Angiogenesis plays a pivotal role in splanchnic hyperaemia and portosystemic collateral formation in cirrhosis. Endothelin-1 (ET-1), an endothelium-derived vasoconstrictor, has also been implicated in the pathogenesis of cirrhosis and portal hypertension. Design This study aimed to survey the influences of ET-1 in cirrhosis-related angiogenesis. Common bile duct ligation was performed on Spraque–Dawley rats to induce cirrhosis. Since the 14th day after the operation, rats randomly received distilled water (DW, control), bosentan [a nonselective ET receptor (ETR) blocker] or ambrisentan (a selective ET A R blocker) for 4 weeks. On the 43rd day, portal and systemic haemodynamics, liver biochemistry, portosystemic shunting degree, mesenteric vascular density, mRNA and/or protein expressions of relevant angiogenic factors were evaluated. Results In cirrhotic rats, bosentan significantly reduced portal pressure. Ambrisentan did not influence haemodynamics and liver biochemistry. Both of them significantly improved the severity of portosystemic collaterals and decreased the mesenteric vascular density. Compared with the DW-treated cirrhotic rats, splenorenal shunt and mesenteric inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX2), vascular endothelial growth factor mRNA expressions and mesenteric iNOS, COX2, VEGF, phospho-VEGF receptor 2, Akt and phospho-Akt protein expressions were down-regulated in both groups. Conclusions In rats with liver cirrhosis, both nonselective and selective ET A R blockade ameliorate the severity of portosystemic shunting and mesenteric angiogenesis via the down-regulation of VEGF pathway and relevant angiogenic factors. ET receptors may be targeted to control the severity of portosystemic collaterals and associated complications in cirrhosis. Keywords Angiogenesis, endothelin-1, liver cirrhosis, portosystemic collaterals, vascular endothelial growth factor. Eur J Clin Invest 2016; 46 (6): 572–580 Introduction Liver cirrhosis increases intrahepatic resistance through fibrosis and vasoconstriction. Taken the hyperdynamic circu- lation with increased portal blood flow together, portal hypertension and portosystemic collaterals develop gradually [1]. The immature collateral vessels are prone to rupture with high morbidity and mortality, such as gastroesophageal varices. Traditionally, the increase in splanchnic inflow was considered a consequence of vascular dilatation in which nitric oxide (NO) plays a role [1]. Nevertheless, recent studies have proposed that angiogenesis, the generation of new blood vessels, is involved in the process. Inhibition of pathological angiogenesis effectively ameliorated severity of shunting [2]. Furthermore, even vascular contractility was unaffected, alleviation of angiogenesis still decreased shunting degree by suppression of vascular endothelial growth factor (VEGF), a potent angiogenic factor [3]. Therefore, angiogenic factor modulation can be a feasible strategy to alleviate mesenteric angiogenesis and portosystemic collaterals. Endothelin (ET) participates in pathogenesis of portal hypertension. The ET family consists of three 21-amino acid 572 ª 2016 Stichting European Society for Clinical Investigation Journal Foundation DOI: 10.1111/eci.12636 ORIGINAL ARTICLE