Fibrotic remodeling of colonic tunica muscularis is associated with vascular network activation in ulcerative colitis

Abstract

Intestinal fibrosis in inflammatory bowel disease is a dynamic, multifactorial process, which involve multiple cell types and interconnected events [1]. Angiogenesis is a hallmark of active gut disease and closely related to fibrogenetic processes. Endothelial cells and pericytes of neovessels have been found to be able to differentiate into fibroblasts and can be considered good candidates for fibrogenesis also in the intestinal tract [2]. This study was aimed to study whether the fibrotic processes occurring within the tunica muscularis of UC patients are associated with vascular remodeling. Full-thickness left colonic samples were obtained from patients with established, severe and pharmacologically unresponsive UC, who underwent bowel resection. Routine histology, histochemistry and immunohistochemistry were conducted in paraffin cross-sections. Collagen and elastic fiber distribution was evaluated within the tunica muscularis by both histochemical and immunohistochemical assays. The vascular network pattern was analyzed by revealing the expression of CD31, CD105 and nestin by immunofluorescence applied to laser confocal microscopy. A significant increase in collagen fibers and a decrease in elastin content were detected in the tonaca muscularis of UC inflamed colon, as compared with controls. In particular, enhanced collagen deposition were found at level of the longitudinal muscle and circular muscle layer, and in perivascular spaces. By contrast, elastic fiber pattern was significantly decreased throughout the whole muscle compartment. Increased blood vessel density was observed in the colonic tunica muscularis of UC samples compared with samples from healthy control individuals. In particular, the neovessels of inflamed colon showed the activation of both endothelial cells and pericytes, which overexpressed CD105 and nestin, respectively. A significant vascular remodelling (i.e., angiogenesis, endothelial proliferation and pericyte activation) has been observed in the fibrotic tunica muscularis of colon from UC patients. On the basis of the present findings, it is possible to argue that cells of newly formed vessels within the tunica muscularis may contribute to the UC-associated fibrosis by cell transition to mesenchymal phenotype.