Heldens Anneleen, Casteleyn Christophe, Onghena Louis, Antwi Milton, Neyt Sara, Descamps Benedicte, Vanhove Christian, Verhelst Xavier, Raevens Sarah, Van Vlierberghe Hans, Devisscher Lindsey, De Bruyne Ruth, Junien Jean-Louis, Wettstein Guillaume, Geerts Anja, Lefere Sander
Department of Internal Medicine and Pediatrics, Hepatology Research Unit, Ghent University, Ghent, Belgium; Liver Research Center Ghent, Ghent University, Ghent University Hospital, Ghent, Belgium.
Department of Morphology, Imaging, Orthopedics, Rehabilitation and Nutrition, Ghent University, Ghent, Belgium.
Biomed Pharmacother. 2025 Feb;183:117826. doi: 10.1016/j.biopha.2025.117826. Epub 2025 Jan 12.
Portal hypertension (PH) can cause severe complications in patients with advanced chronic liver disease (aCLD). The pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist lanifibranor reduces portal pressure in preclinical models of aCLD. Since the effect on PH might be secondary to fibrosis improvement, we investigated the effect of lanifibranor on PH, hepatic and splanchnic angiogenesis in mouse models of fibrotic and prehepatic non-fibrotic PH. Mice with fibrotic PH (common bile duct ligation; CBDL) and prehepatic PH (partial portal vein ligation; PPVL) received daily lanifibranor/vehicle for 14 or 7 days, respectively. Hemodynamics, serum, hepatic and mesenteric histology, and hepatic, mesenteric and liver sinusoidal endothelial cells (LSEC) gene expression levels were analyzed. Vascular corrosion casts of the venous mesenteric and hepatic vasculature were analyzed using scanning electron microscopy and µCT. Portal pressure was increased in CBDL mice. Lanifibranor treatment demonstrated a dose-dependent trend towards decreasing the elevated portal pressure, and reduced fibrosis. Hepatic mRNA levels of inflammatory, fibrotic and angiogenic markers were significantly downregulated in lanifibranor-treated CBDL mice. LSEC dysfunction was improved by lanifibranor. Compared to CBDL mice, portal pressure was more extensively elevated in PPVL mice, which was significantly reduced by lanifibranor. Superior mesenteric artery blood flow, which was increased in vehicle-treated PPVL mice, tended to decrease by lanifibranor. The expansion of the mesenteric vasculature and mesenteric protein level of angiogenetic markers in PPVL mice were reduced after lanifibranor. In conclusion, lanifibranor improves PH, independently from fibrosis reduction, potentially through reducing the venous mesenteric vasculature expansion and intrahepatic angiogenesis, and ameliorating LSEC function.
门静脉高压（PH）可在晚期慢性肝病（aCLD）患者中引发严重并发症。全过氧化物酶体增殖物激活受体（pan-PPAR）激动剂拉尼贝特在aCLD临床前模型中可降低门静脉压力。由于对PH的影响可能继发于纤维化改善，我们在纤维化和肝前非纤维化PH小鼠模型中研究了拉尼贝特对PH、肝脏和内脏血管生成的影响。患有纤维化PH（胆总管结扎；CBDL）和肝前PH（部分门静脉结扎；PPVL）的小鼠分别每日接受拉尼贝特/赋形剂治疗14天或7天。分析血流动力学、血清、肝脏和肠系膜组织学以及肝脏、肠系膜和肝窦内皮细胞（LSEC）基因表达水平。使用扫描电子显微镜和μCT分析静脉肠系膜和肝血管系统的血管铸型。CBDL小鼠的门静脉压力升高。拉尼贝特治疗显示出降低升高的门静脉压力的剂量依赖性趋势，并减少了纤维化。在接受拉尼贝特治疗的CBDL小鼠中，炎症、纤维化和血管生成标志物的肝脏mRNA水平显著下调。拉尼贝特改善了LSEC功能障碍。与CBDL小鼠相比，PPVL小鼠的门静脉压力升高更为广泛，拉尼贝特可显著降低该压力。在接受赋形剂治疗的PPVL小鼠中增加的肠系膜上动脉血流量，拉尼贝特使其有降低趋势。拉尼贝特治疗后，PPVL小鼠肠系膜血管系统的扩张和肠系膜血管生成标志物的蛋白水平降低。总之，拉尼贝特可改善PH，独立于纤维化的减轻，可能是通过减少肠系膜静脉血管系统扩张和肝内血管生成，以及改善LSEC功能。
