Mechanosensing Piezo1 mediates gut-vascular barrier dysfunction in portal hypertension and promotes deterioration of liver cirrhosis

Abstract Objectives Gut-vascular barrier (GVB) disruption in cirrhotic portal hypertension (PH) exacerbates hepatic and systemic damage via the gut-liver-organ axis, but the underlying mechanism is unclear. The mechanosensitive channel Piezo1, known to regulate endothelial homeostasis, may mediate GVB dysfunction, requiring validation. Methods Carbon tetrachloride (CCl 4 )-induced liver cirrhosis and partial portal vein ligation (PPVL)-induced pre-hepatic PH model were established in Piezo1 flox/flox and endothelial cells (ECs)-specific Piezo1-deficient (Piezo1 △EC ) mice. Portal pressure, GVB permeability, intestinal and systemic inflammation, and Piezo1 expression in mucosal ECs were measured. Cultured intestinal microvascular ECs were treated with the Piezo1 agonist Yoda1 or hydrostatic pressure to investigate Piezo1-mediated endothelial barrier regulation. Results PH induced significant GVB breakdown in CCl 4 and PPVL mice, presented as increased permeability from the gut-to-blood and also leakage from blood-to-gut, accompanied by increased Piezo1 and VEGFR2 expression in ECs, along with systemic and intestinal inflammation and leaky epithelium. These effects were reversed in Piezo1 △EC mice, and Piezo1 knockout in ECs reduced VEGFR2 expression which in turn inhibited intestinal leakage and inflammatory infiltration, and meanwhile improved systemic inflammation. Moreover, Yoda1 or hydrostatic pressure promoted VEGFR2 phosphorylation and ECs monolayer disruption, blocked by siRNA of Piezo1 or Vegfr2 . Conclusion Endothelial Piezo1 contributed to GVB dysfunction in PH via VEGFR2 pathway. The outward and inward hyper-permeability of GVB in PH may initiate the intestinal inflammation and trigger epithelial leakage, and further cause systemic inflammation and injury. Therefore, Piezo1-mediated GVB damage may be a novel explanation and potential therapeutic target for deterioration of liver cirrhosis with PH.