Intestinal endothelial dysfunction may have a role in the development of myenteric nerve damage in a rat model of diabetes mellitus

Background: Our previous studies have demonstrated that the nitrergic subpopulation of myenteric neurons is especially susceptible to neurodegenerative changes in a streptozotocine-induced rat model of diabetes. The loss of modulatory role of endothelium in capillaries supplying the myenteric plexus has been proposed as a potential mechanism underlying enteric neuropathy. Aim of the present studies was to elucidate the relationship between the diabetes-associated neuronal and vascular damage. Therefore we investigated the quantitative change in nitrergic myenteric neurons, the change in the thickness of basal lamina (BL), the Caveolin-1 (CAV-1) and endothelial nitric oxide synthase (eNOS) expression in capillary endothel in the vicinity of the myenteric plexus. Materials and Methods: Ten weeks after the onset of diabetes, gut segments of control, streptozotocin-induced diabetic and insulin-treated diabetic rats were processed. The effects of diabetes and insulin replacement on density of nitrergic neurons were evaluated by NADPH-diaphorase histochemistry. The thickness of BL was measured by morphometry and quantitative features of CAV-1 and eNOS was investigated by postembedding immunohistochemistry. Results: Regionally different susceptibilities of nitrergic myenteric neurons to diabetic damage and their different responsiveness to insulin treatment have been demonstrated. Nitrergic neuronal density decreased by 35% in the duodenum and by 15% in the ileum. Insulin treatment partially prevented the cell loss in the jejunum and completely in the colon. Region-specific thickening of BL and overexpression of CAV-1 and eNOS were documented in diabetic animals, while immediate insulin treatment had a prophylactic effect. Conclusions: Our data indicate that endothelial dysfunction in the intestine can be an additional pathogenetic factor for the development of neurodegenerative changes in the enteric nervous system and associated deranged intestinal motility demonstrated previously in this model. Grant support: UMFT-TÁMOP-4.2.2–08/01