Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy.
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.


CONCLUSIONS
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.
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.|Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.
Eilidh
E
Somers
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
Robert D
RD
Lees
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
Katie
K
Hoban
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
James N
JN
Sleigh
Dubowitz Neuromuscular Center, Institute of Child Health, University College London, London, United Kingdom.
Haiyan
H
Zhou
Dubowitz Neuromuscular Center, Institute of Child Health, University College London, London, United Kingdom.
Francesco
F
Muntoni
Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
Kevin
K
Talbot
Center for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.|Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.
Thomas H
TH
Gillingwater
Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.|Euan MacDonald Center for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, United Kingdom.
Simon H
SH
Parson
D000818:Animals; D000831:Animals, Newborn; D002196:Capillaries / Q000254:growth & development / Q000473:pathology*; D002675:Child, Preschool; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000209:etiology / Q000378:metabolism*; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply*; D009134:Muscular Atrophy, Spinal / Q000150:complications / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000098:blood supply* / Q000378:metabolism; D014652:Vascular Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology