No 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.

Erythropoietin (Ep) is a glycoprotein hormone that is responsible for mammalian red blood cell production. Adult rat liver regenerating 48-72 h after hepatectomy (hepx) produces elevated levels of Ep in response to hypoxia when compared to sham-operated, anephric hypoxic controls. A factor, termed hepatopoietin (Hp), found in the serum of hepx rats, is capable of stimulating hepatic Ep production when administered to normal rats 18 h prior to hypoxic exposure. Although the hepatic vein is the most potent source of this factor, Hp can also be demonstrated in the systemic arterial circulation. Bilateral nephrectomy (nephrx) of the donor hepx animal 24 h prior to bleeding abolishes this variation, and highest Ep levels are noted when serum from a hepx and nephrx rat is administered to animals immediatley after nephrx and 18 h before hypoxic exposure. Serum derived from hepx male rats displays a greater ability to evoke hepatic Ep production in normal recipients than serum from similarly treated female rats. Regardless of the sex of the hepx donor, Ep elaboration after hypoxia is highest in male recipients. The results indicate that there is a sexual variation in the production of Hp as well as Ep.