Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
Am J Physiol Gastrointest Liver Physiol. 2021 May 1;320(5):G768-G779. doi: 10.1152/ajpgi.00047.2021. Epub 2021 Mar 3.
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 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. 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.
线粒体神经胃肠脑肌病（MNGIE）是一种罕见的常染色体隐性遗传病，由胸苷磷酸化酶（TP）酶缺陷引起。由于接受 TP 替代治疗的患者的胃肠道变化不会恢复，因此可以推测其他尚未探索的机制有助于 MNGIE 的病理生理学。因此，我们专注于局部 TP 血管生成潜力，这在 MNGIE 中从未被考虑过。在这项研究中，我们研究了从 MNGIE 患者收集的空肠全层活检中的肠黏膜下微循环，并研究了缺氧对纤维化和肠神经元密度的影响。奥辛染色用于根据血管大小计数血管。使用天狼星红和快速绿方法评估纤维化。通过缺氧诱导因子-1α（HIF-1α）和血管内皮生长因子（VEGF）蛋白表达分别确定缺氧和新生血管形成。神经元特异性烯醇化酶用于标记肠神经元。与对照组相比，MNGIE 患者的血管组织面积减少，但黏膜下血管/mm 增加两倍，小血管增加，中、大血管减少。VEGF 阳性血管、纤维化指数和 HIF-1α 蛋白表达增加，而纵肌层厚度减少，神经节间距离增加，肌间神经元数量减少。我们证明了 MNGIE 患者的胃肠道存在血管病变。新生血管变化，如空肠黏膜下小血管的丰富程度，以及缺氧为解释 MNGIE 中的神经肌肉改变、血管破裂和缺血异常提供了形态学基础。线粒体神经胃肠脑肌病（MNGIE）的特征是胸苷磷酸化酶的遗传驱动缺陷，胸苷磷酸化酶是一种多功能酶，在血管生成中也发挥作用。事实上，胃肠道大出血是 MNGIE 的危及生命的并发症。因此，我们专注于空肠黏膜下血管，并显示出肠道微血管病作为该疾病的一个新特征。值得注意的是，血管变化与神经肌肉异常相关，这可能解释肠道功能障碍，并有助于在 MNGIE 中开发未来的治疗方法。
