Hypoxia Bi-directionally Regulates Gut Vascular Barrier through HIF-1α-dependent Mechanism in vitro

Abstract

Objective: The gut vascular barrier (GVB) is the key checkpoint for pathogens to enter the blood circulation through the intestine, which is crucial for maintaining the intestinal barrier function. However, the effect and molecular mechanism of hypoxia on GVB remains unclear. Here, we show a role of the transcription factor hypoxia inducible factor-1α (HIF-1α) in hypoxia-induced bi-directional regulation of GVB. Approach and Results: An in vitro GVB model composed of rat intestinal microvascular endothelial cells was studied. Evans blue-albumin efflux assay showed that the experimentally severe hypoxia induced by cobalt chloride (500 µM, 24 h) markedly disrupted the GVB in vitro, while mild hypoxia induced by cobalt chloride (500 µM, 6 h) evidently enhanced the GVB, revealing hypoxia-induced bi-directional regulation of the GVB for the first-time. Importantly, knockdown of HIF-1α largely abolished the bi-directional changes of GVB caused by hypoxia. Furthermore, experimentally severe hypoxia exacerbated the inflammatory GVB disruption induced by LPS or TNF-α, while the mild hypoxia promoted the repair. Conclusion: Collectively, our data indicate that hypoxia bi-directionally regulates GVB in a HIF-1α-dependent manner.