Rat models for Portosinusoidal Vascular Disease

Background: Porto-Sinusoidal Vascular Disorder (PSVD) involves a group of rare vascular liver diseases of unknown etiology that leads to the development of portal hypertension and its life-threatening complications. Its pathophysiology is not well understood and animal models described to date do not fully recapitulate human disease. Methods: We developed 3 different PSVD rat models by either immunosensitization (repetitive intraportal LPS or intramuscular spleen extract injections) or toxic (combination of FOLFOX and a selenium-enriched diet, Selfox model) treatment and characterized them at hemodynamic, histological, biochemical and transcriptional levels. We compared these results to human data. Results: All three models developed significant portal hypertension, while only the LPS and the Selfox models displayed PSVD specific and non-specific histological alterations in the absence of cirrhosis. Transcriptional comparison between rat animal models and human data showed both LPS and Selfox models recapitulate the main transcriptional alterations observed in humans, especially regarding hemostasis, oxidative phosphorylation and cell cycle regulation. Reproducibility and feasibility was higher for the Selfox model. Conclusions: The Selfox rat model faithfully reproduces the main alterations described in PSVD. Its use as a preclinical model for drug testing in progressing PSVD can be a significant step forward towards development of new therapeutic targets for this rare condition. Overall design: There are three groups of rats. Control rats did not receive any treatment. For LPS rats, rats were anesthetized with isofluorane. Animals were then laparotomized and permanent access to the portal vein was obtained with the introduction of an indwelling to the gastric vein right above the ileocholic vein that would extend to the back of the rat where it was fixed with a harness, leaving it accessible for successive injections. Rat's abdomen was then sewed. Animals received a bolus of 1 mg/kg of LPS twice a week for a period of 8 weeks. For Oxa (Selfox rats), rats were fed ad libitum with the selenium-enriched diet during 8 weeks. During this time, rats were also injected intravenously with a solution of oxaliplatin (3 mg/kg) + 5-FU (25 mg/kg) + folinic acid (45 mg/kg) once per week, for a total of 8 injections.