Eddama, Mohammad; (2018) The angiogenic characterisation of mesenteric adipose tissue in Crohn’s Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Introduction Crohn’s disease (CD) has a distinct feature of mesenteric adipose tissue (AT) expansion, the role of which is unclear. This study hypothesises that the angiogenic mechanisms in CD mesenteric AT are dysregulated. Methods Mesenteric, subcutaneous and omental AT were harvested from 30 patients who underwent ileocolic resection, including 19 CD and 11 controls. Angiogenic mechanisms were examined by: histology and immunohistochemistry; real time polymerase chain reaction (RT PCR) gene array; and enzyme linked immunosorbent assay (ELISA). ELISA was also used to assess the level of interleukin-6 (IL6) and vascular endothelial growth factor (VEGF) secretion by tissue over an incubation period of 36 hours. Angiogenic capacity was measured by matrigel angiogenic assay. Results Microvascular density (MVD) was significantly (p<0.01) higher in CD mesenteric AT (mean=29, SD=20) than control (mean=19, SD=12). Hypoxia inducible factor-1 (HIF1) staining was higher in CD mesenteric AT (n=22, 67%) than control (n=18, 22%) (Χ2(2)=11.2, p<0.01). RT-PCR array confirmed that 47 (56%) of the angiogenic genes were >2-folds down-regulated in CD mesenteric AT. Correlation matrix showed significantly more negative correlations in CD mesenteric AT (n=711, 20%) than control (n=109, 3%) (X2(1)=501, p<0.0001). The mean-z-score for negative correlation was significantly (p<0.0001) stronger in CD mesenteric AT (mean=0.3, SD=0.2) than control (mean=0.1, SD=0.1). CD mesenteric AT protein expression of IL6 (mean=21 pg/mg, SD=18) and VEGF (mean=34 pg/mg, SD=19) were significantly (p<0.05 and p<0.01) lower than control (mean=39 pg/mg, SD=43) and (mean=57 pg/mg, SD=43) respectively. In-vitro secretion of IL6 and VEGF was similar in CD and control AT. Vascular sprouting was statistically significantly (p<0.01) lower in CD mesenteric AT (mean=3.2, SD=3) than control (mean=5.2, SD=4.1). Conclusion CD mesenteric AT demonstrated dysregulated angiogenesis and significantly lower capacity for vascular sprouting in comparison to control. The observed dysregulated angiogenesis may partly explain the role of mesentery in the perpetuation of CD inflammation.

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