CXCL5 is required for angiogenesis, but not structural adaptation after small bowel resection

Abstract

Purpose: Intestinal adaptation is the compensatory response to massive small bowel resection (SBR) and characterized by lengthening of villi and deepening of crypts, resulting in increased mucosal surface area. Previous studies have demonstrated increased villus capillary blood vessel density after SBR, suggesting a role for angiogenesis in the development of resection-induced adaptation. Since we have previously shown enhanced expression of the pro-angiogenic chemokine CXCL5 after SBR, the purpose of this study was to determine the effect of disrupted CXCL5 expression on intestinal adaptation. Methods: CXCL5 knock-out (KO) and C57BL/6 wild type (WT) mice were subjected to either a 50% proximal SBR or sham operation. Ileal tissue was harvested on postoperative day 7. To assess for adaptation, villus height and crypt depth were measured. Submucosal capillary density was measured by CD31 immunohistochemistry. Results: Both CXCL5-KO and WT mice demonstrated normal structural features of adaptation. Submucosal capillary density increased in the WT but not in the KO mice following SBR. Conclusion: CXCL5 is required for increased intestinal angiogenesis during resection-induced adaptation. Since adaptive villus growth occurs despite impaired CXCL5 expression and enhanced angiogenesis, this suggests that the growth of new blood vessels is not needed for resection-induced mucosal surface area expansion following massive SBR.

The effect of impaired angiogenesis on intestinal function following massive small bowel resection

“…This process is also seen within the small intestine after SBR in both the lamina propria of the adapted villus and submucosal compartment [4, 5]. We have previously been able to hinder this angiogenic response through the selective blockade of salivary-derived vascular endothelial growth factor (VEGF), resulting in adaptive impairment [18].…”

“…This process involves critical and compensatory alterations that increase the intestinal absorptive area via increased enterocyte proliferation leading to the lengthening of villi and deepening of crypts [1–3]. In addition to these morphologic changes, we have previously reported resection-induced increased neovascularization within the adapted intestinal villi and submucosal compartments [4, 5]. This angiogenic response is preceded by increased expression of the chemokine C-X-C ligand 5 (CXCL5) protein [4, 6].…”

“…It has been shown to play a role in neutrophil homeostasis at mucosal sites and thus overexpressed in conditions such as NEC and inflammatory bowel disease [7–9]. Mice lacking this chemokine have normal structural features of adaptation, but lack the reactive angiogenesis after SBR [5]. …”

Both epidermal growth factor and insulin-like growth factor receptors are dispensable for structural intestinal adaptation

“…Immunohistochemistry staining with cd31 was performed using our previously published protocol [19]. The number of cd31-stained vessels was counted in the submucosal layer per high power field (40x).…”

Nutritional strategies to enhance adaptation in intestinal failure

“…Expression of absorptive transporters, such as the sodium-glucose cotransporter SGLT1, the Na/H-exchangers NHE2 and NHE3, as well as the Na/K-ATPase, increases [8][9][10]. It is of note that at least under experimental conditions morphological and functional changes are not strictly coupled and may even be uncoupled [11,12]. Transit time is also downregulated.…”