Portal hypertension is a common clinical symptom of digestive disorders. With an increase in portal pressure, the portal vein will continue to dilate. We aimed to determine whether continuous stretch induced by portal hypertension may impair the function of endothelial cells (ECs) in the portal vein and aggravate the progress of portal hypertension and explore its mechanism. ECs were cultured on an elastic silicone membrane and subjected to continuous uniaxial stretch. Apoptosis and expression of TGF-β in ECs under stretch were measured. We found that sustained stretch induced the apoptosis of ECs in a stretch length-dependent manner. Compared with the control, continuous stretch increased the nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression and damaged the mitochondria, resulting in an evident increase in reactive oxygen species (ROS) levels; pretreatment with gp91ds-tat or MitoTEMPO decreased the ROS level in the intracellular levels. N-acetyl-cysteine (NAC) treatment before stretch not only reduced ROS levels but also mitigated the apoptosis of ECs; simvastatin had similar effects through targeting NOX2 and mitochondria. During the stretch, the phosphorylation of p38 mitogen-activated protein kinase (P38MAPK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB) was obviously increased; pretreatment with P38MAPK or JNK inhibitors decreased the phosphorylation of NF-κB and TGF-β expression. Pyrrolidine dithiocarbamate (PDTC) treatment before stretch also reduced TGF-β expression. After pretreatment with NAC, the phosphorylation of P38MAPK, JNK, and NF-κB and TGF-β expressions in ECs under stretch was suppressed; similar results were observed in simvastatin-treated ECs. This study demonstrated that simvastatin could mitigate EC apoptosis and TGF-β upregulation induced by continuous stretch by reducing the level of ROS.

Background Oxaliplatin, used as first-choice treatment for colorectal cancer (CRC), induces sinusoidal endothelial injury and portal hypertension. This study investigated the characteristics of oxaliplatin-induced portal hypertension and evaluated the efficacy of endoscopic management of gastroesophageal variceal bleeding. Methods We performed a retrospective, multicenter, case-control study between January 2010 and December 2018. Patients who received oxaliplatin-based chemotherapy after CRC surgery and presented with portal hypertension and gastroesophageal varices were compared with consecutive patients with hepatitis B-related cirrhotic portal hypertension receiving endoscopic treatment for variceal bleeding. Results 39 patients with oxaliplatin-induced portal hypertension were identified, 35 of whom had a history of variceal bleeding. The median period between start of oxaliplatin-based chemotherapy and the occurrence of varices was 50.4 months (n = 39). A total of 26 patients with oxaliplatin-related portal hypertension and 230 patients with hepatitis B-related portal hypertension underwent endoscopic treatment. Kaplan-Meier analysis revealed that the 1-year rebleeding rate was significantly higher in the oxaliplatin group than in the hepatitis B group (43.3 % vs. 19.0 %, P = 0.001). Multivariable Cox regression analysis showed that oxaliplatin-based chemotherapy was an independent factor for 3-year rebleeding (hazard ratio [HR] 2.46, 95 % confidence interval [CI] 1.24–4.87; P = 0.01) and 3-year overall mortality (HR 9.43, 95 %CI 2.32–38.31; P = 0.002). Conclusions Oxaliplatin-related portal hypertension was characterized by massive ascites, splenomegaly, gastric varices, concomitant arterioportal fistula, and relatively normal liver function. Endoscopic treatment to prevent variceal rebleeding in these patients was unsatisfactory compared with endoscopic treatment for hepatitis B-related portal hypertension.