Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy
| Autor: | Francesco Muntoni, Robert D. Lees, James N. Sleigh, Thomas H. Gillingwater, Simon H. Parson, Haiyan Zhou, Eilidh Somers, Katie Hoban, Kevin Talbot |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Pathology medicine.medical_specialty Cord business.industry Skeletal muscle Spinal muscular atrophy SMN1 Hypoxia (medical) Motor neuron medicine.disease Spinal cord SMA 03 medical and health sciences 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure Neurology medicine Neurology (clinical) medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | Annals of Neurology. 79:217-230 |
| ISSN: | 0364-5134 |
| DOI: | 10.1002/ana.24549 |
| Popis: | Objective Spinal muscular atrophy (SMA) is a major inherited cause of infant death worldwide. It results from mutations in a single, ubiquitously expressed gene (SMN1), with loss of lower motor neurons being the primary pathological signature. Systemic defects have also been reported in SMA patients and animal models. We investigated whether defects associated with the vasculature contribute to motor neuron pathology in SMA. Methods Development and integrity of the capillary bed was examined in skeletal muscle and spinal cord of SMA mice, and muscle biopsies from SMA patients and controls, using quantitative morphometric approaches on immunohistochemically labeled tissue. Pimonidazole hydrochloride–based assays were used to identify functional hypoxia. Results The capillary bed in muscle and spinal cord was normal in presymptomatic SMA mice (postnatal day 1), but failed to match subsequent postnatal development in control littermates. At mid- and late-symptomatic time points, the extent of the vascular architecture observed in two distinct mouse models of SMA was ∼50% of that observed in control animals. Skeletal muscle biopsies from human patients confirmed the presence of developmentally similar, significant vascular depletion in severe SMA. Hypovascularity in SMA mouse spinal cord was accompanied by significant functional hypoxia and defects in the blood–spinal cord barrier. Interpretation Our results indicate that vascular defects are a major feature of severe forms of SMA, present in both mouse models and patients, resulting in functional hypoxia of motor neurons. Thus, abnormal vascular development and resulting hypoxia may contribute to the pathogenesis of SMA. Ann Neurol 2016;79:217–230 |
| Databáze: | OpenAIRE |
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