Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy
Eilidh Somers BSc, PhD
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorRobert D. Lees RD, BMedSci
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorKatie Hoban BSc
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorJames N. Sleigh MBiol, DPhil
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
Search for more papers by this authorHaiyan Zhou PhD
Dubowitz Neuromuscular Center, Institute of Child Health, University College London, London, United Kingdom
Search for more papers by this authorFrancesco Muntoni MD
Dubowitz Neuromuscular Center, Institute of Child Health, University College London, London, United Kingdom
Search for more papers by this authorKevin Talbot DPhil
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
Search for more papers by this authorThomas H. Gillingwater BSc, PhD
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorCorresponding Author
Simon H. Parson BSc, PhD
Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom
Address correspondence to Dr Simon H. Parson, Suttie Center, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom. E-mail: [email protected]Search for more papers by this authorEilidh Somers BSc, PhD
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorRobert D. Lees RD, BMedSci
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorKatie Hoban BSc
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorJames N. Sleigh MBiol, DPhil
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
Search for more papers by this authorHaiyan Zhou PhD
Dubowitz Neuromuscular Center, Institute of Child Health, University College London, London, United Kingdom
Search for more papers by this authorFrancesco Muntoni MD
Dubowitz Neuromuscular Center, Institute of Child Health, University College London, London, United Kingdom
Search for more papers by this authorKevin Talbot DPhil
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
Search for more papers by this authorThomas H. Gillingwater BSc, PhD
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom
Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom
Search for more papers by this authorCorresponding Author
Simon H. Parson BSc, PhD
Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom
Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom
Address correspondence to Dr Simon H. Parson, Suttie Center, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, United Kingdom. E-mail: [email protected]Search for more papers by this authorAbstract
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
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