Abstract
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
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
| Original language | English |
|---|---|
| Pages (from-to) | 217-230 |
| Number of pages | 14 |
| Journal | Annals of Neurology |
| Volume | 79 |
| Issue number | 2 |
| Early online date | 13 Jan 2016 |
| DOIs | |
| Publication status | Published - Feb 2016 |
Bibliographical note
AcknowledgmentS.H.P. is funded by The Euan MacDonald Center for Motor Neurone Disease Research and The SMA Trust. T.H.G. is funded by Muscular Dystrophy UK and The SMA Trust. K.T. is funded by The SMA Trust and the Motor Neurone Disease Association. H.Z. is funded by National Institute for Health Research and Great Ormond Street Hospital Biomedical Research Center, and F.M. is funded by the Medical Research Council and Great Ormond Street Hospital Charity.
The MRC Center for Neuromuscular Diseases BioBank London (CNMD_BBL) is gratefully acknowledged.
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Simon Parson
- School of Medicine, Medical Sciences & Nutrition, Medical Education - Regius Chair of Anatomy
- The Suttie Centre - Anatomy
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