Evidence of enteric angiopathy and neuromuscular hypoxia in patients with mitochondrial neurogastrointestinal encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. Since gastrointestinal changes do not revert in patients undergone TP replacement therapy, one can postulate that other unexplored mechanisms contribute to MNGIE pathophysiology. Hence, we focused on the local TP angiogenic potential that has never been considered in MNGIE. In this study, we investigated the enteric submucosal microvasculature and the effect of hypoxia on fibrosis and enteric neurons density in jejunal full-thickness biopsies collected from MNGIE patients. Orcein staining was used to count blood vessels based on their size. Fibrosis was assessed using the Sirius Red and Fast Green method. Hypoxia and neoangiogenesis were determined via hypoxia-inducible-factor-1a (HIF-1a) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron specific enolase was used to label enteric neurons. Compared to controls, MNGIE patients showed a decreased area of vascular tissue, but a two-fold increase of submucosal vessels/mm2 with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index and HIF-1a protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased inter-ganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of MNGIE patients. Neoangiogenetic changes, as detected by the abundance of small size vessels in the jejunal submucosa, along with hypoxia provide a morphological basis to explain neuromuscular alterations, vasculature breakdown and ischemic abnormalities in MNGIE.