| Autor: |
Boschetti E; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy., D'Angelo R; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC interaziendale Clinica Neurologica Metropolitana (NeuroMet), Neurologia AOU S. Orsola-Malpighi, Bologna, Italy., Tardio ML; IRCCS St. Orsola-Malpighi Hospital, Bologna, Italy., Costa R; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy., Giordano C; Department of Medico-Surgical Sciences and Biotechnologies, University 'La Sapienza', Roma, Italy., Accarino A; Digestive System Research Unit, University Hospital Vall d'Hebron; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD); Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain., Malagelada C; Digestive System Research Unit, University Hospital Vall d'Hebron; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD); Departament de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain., Clavenzani P; Department of Veterinary Medical Sciences, University of Bologna, Bologna, Italy., Tugnoli V; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy., Caio G; Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy., Righi V; Department of Life Quality Studies, University of Bologna, Bologna, Italy., Garone C; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy., D'Errico A; IRCCS St. Orsola-Malpighi Hospital, Bologna, Italy., Cenacchi G; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy., Dotti MT; Department of Medical, Surgical and Neurological Sciences, University of Siena, Siena, Italy., Stanghellini V; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy., Sternini C; Digestive-Disease-Division, Departments of Medicine and Neurobiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California., Pironi L; Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy., Rinaldi R; IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC interaziendale Clinica Neurologica Metropolitana (NeuroMet), Neurologia AOU S. Orsola-Malpighi, Bologna, Italy., Carelli V; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy., De Giorgio R; Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy. |
| Abstrakt: |
Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disease caused by thymidine phosphorylase (TP) enzyme defect. As 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 patients with MNGIE. 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-1α (HIF-1α) and vascular endothelial cell growth factor (VEGF) protein expression, respectively. Neuron-specific enolase was used to label enteric neurons. Compared with controls, patients with MNGIE showed a decreased area of vascular tissue, but a twofold increase of submucosal vessels/mm 2 with increased small size and decreased medium and large size vessels. VEGF positive vessels, fibrosis index, and HIF-1α protein expression were increased, whereas there was a diminished thickness of the longitudinal muscle layer with an increased interganglionic distance and reduced number of myenteric neurons. We demonstrated the occurrence of an angiopathy in the GI tract of patients with MNGIE. 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. NEW & NOTEWORTHY Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is characterized by a genetically driven defect of thymidine phosphorylase, a multitask enzyme playing a role also in angiogenesis. Indeed, major gastrointestinal bleedings are life-threatening complications of MNGIE. Thus, we focused on jejunal submucosal vasculature and showed intestinal microangiopathy as a novel feature occurring in this disease. Notably, vascular changes were associated with neuromuscular abnormalities, which may explain gut dysfunction and help to develop future therapeutic approaches in MNGIE. |
