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Intestinal preservation for transplantation is accompanied by hypoperfusion with long periods of ischemia with total blood cessation and absolute withdrawal of oxygen leading to structural damage. The application of intraluminal oxygen has been successfully tested in small-animal series during storage and transport of the organ but have been so far clinically unrelatable. In this study, we tested whether a simple and clinically approachable method of intraluminal oxygen application could prevent ischemic damage in a large animal model, during warm ischemia time. We utilised a local no-flow ischemia model of the small intestine in pigs. A low-flow and high-pressure intraluminal oxygen deliverance system was applied in 6 pigs and 6 pigs served as a control group. Mucosal histopathology, hypoxia and barrier markers were evaluated after two hours of no-flow conditions, in both treatment and sham groups, and in healthy tissue. Macro- and microscopically, the luminal oxygen delivered treatment group showed preserved small bowel's appearance, viability, and mucosal integrity. A gradual deterioration of histopathology and barrier markers and increase in hypoxia-inducible factor 1-α expression towards the sites most distant from the oxygen application was observed. Intraluminal low-flow, high oxygen delivery can preserve the intestinal mucosa during total ischemia of the small intestine. This finding can be incorporated in methods to overcome small bowel ischemia and improve intestinal preservation for transplantation. [ABSTRACT FROM AUTHOR]

Intestinal ischemia underlies several clinical conditions and can result in the loss of the intestinal mucosal barrier. Ischemia‐induced damage to the intestinal epithelium is repaired by stimulation of intestinal stem cells (ISCs), and paracrine signaling from the vascular niche regulates intestinal regeneration. Here, we identify FOXC1 and FOXC2 as essential regulators of paracrine signaling in intestinal regeneration after ischemia–reperfusion (I/R) injury. Vascular endothelial cell (EC)‐ and lymphatic EC (LEC)‐specific deletions of Foxc1, Foxc2, or both in mice worsen I/R‐induced intestinal damage by causing defects in vascular regrowth, expression of chemokine CXCL12 and Wnt activator R‐spondin 3 (RSPO3) in blood ECs (BECs) and LECs, respectively, and activation of Wnt signaling in ISCs. Both FOXC1 and FOXC2 directly bind to regulatory elements of the CXCL12 and RSPO3 loci in BECs and LECs, respectively. Treatment with CXCL12 and RSPO3 rescues the I/R‐induced intestinal damage in EC‐ and LEC‐Foxc mutant mice, respectively. This study provides evidence that FOXC1 and FOXC2 are required for intestinal regeneration by stimulating paracrine CXCL12 and Wnt signaling. Synopsis: The transcriptional activity of FOXC1 and FOXC2 in lymphatic and blood endothelial cells in the small intestine contributes to vascular repair and intestinal regeneration after ischemia‐reperfusion injury by regulating CXCL12 and R‐spondin3 signalling, respectively. Both FOXC1 and FOXC2 directly regulate the expression of RSPO3 and CXCL12 in the lymphatic/blood vessels near the crypts, respectively.After ischemia‐reperfusion injury, RSPO3 secreted by LECs stimulates the Wnt/β‐catenin signaling pathway and promotes intestinal epithelial regeneration and repair. LEC‐derived RSPO3 also promotes angiogenesis and lymphangiogenesis.After ischemia‐reperfusion injury, BEC‐derived CXCL12 not only regulates angiogenesis but also stimulates CXCR4 expressed on LECs to enhance lymphangiogenesis. [ABSTRACT FROM AUTHOR]