Hypoxia-induced Angiogenesis Rescues Survival from Small for Size Syndrome (SFSS)

Abstract

After extended hepatectomy, hepatocyte proliferation proceeds sinusoidal endothelial cell (SEC) remodeling causing a transient perturbation of the lobular architecture with proliferating hepatocytes forming avascular, hypoxic, clusters. Hypoxia is, thus, considered at the origin of liver dysfunction in SFSS-hepatectomy. Recently, we showed that activation of hypoxia sensors in an upfront SFSS-hepatectomy surged an early angiogenic switch and preserved the sinusoidal architecture with a favorable impact on survival. Aim: to decipher the role hypoxia-induced angiogenesis in SFSS-setting hepatectomy. Methods: we developed a mouse model of SFSS-hepatectomy (PHx-80%) and used PHx-70% as controls. SFSS-hepatectomy mice were submitted to normoxia (inspired oxygen fraction-FiO2: 21%), local hypoxia (hepatic artery ligation (PHx-HAL)), and systemic hypoxia by placing the animals in hypoxic chambers (FiO2: 11%, PHx-HC). We assessed mortality, hepatocyte and liver SEC proliferation. Results: Compared to PHx-70%, PHx-80% showed high mortality rates (68% on postoperative day (POD) 7 (p=0,002)). Hepatocyte proliferation on POD 3 was higher in PHx-80% (p=0,03), while SEC proliferation did not differ, suggesting an amplified disorganization of the regenerating lobule in SFSS-hepatectomy. Compared to normoxic PHx-80%, PHx-HAL tended to have a favorable impact on survival (75% on POD3), while animals subjected to SFSS- hepatectomy and placed into hypoxic chambers showed improved survival (p=0,0007). Hepatocyte proliferation was similar between the hypoxic and normoxic SFSS-liver remnants. However, local and systemic hypoxia significantly triggered early angiogenesis. Conclusions: The current data suggest that hypoxia rescues survival from SFSS. By balancing angiogenesis with hepatocyte proliferation, hypoxia restores the lobular liver architecture allowing an efficient regeneration after major hepatectomy.