Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy

Eilidh Somers, Robert D. Lees, Katie Hoban, James N. Sleigh, Haiyan Zhou, Francesco Muntoni, Kevin Talbot, Thomas H. Gillingwater, Simon H. Parson

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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
Original languageEnglish
Pages (from-to)217-230
Number of pages14
JournalAnnals of Neurology
Volume79
Issue number2
Early online date13 Jan 2016
DOIs
Publication statusPublished - Feb 2016

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Spinal Muscular Atrophy
Blood Vessels
Spinal Cord
Motor Neurons
Skeletal Muscle
Biopsy
Muscles
Muscular Atrophy
Cause of Death
Animal Models
Hypoxia
Pathology
Mutation
Genes

Cite this

Somers, E., Lees, R. D., Hoban, K., Sleigh, J. N., Zhou, H., Muntoni, F., ... Parson, S. H. (2016). Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy. Annals of Neurology, 79(2), 217-230. https://doi.org/10.1002/ana.24549

Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy. / Somers, Eilidh; Lees, Robert D.; Hoban, Katie; Sleigh, James N.; Zhou, Haiyan; Muntoni, Francesco; Talbot, Kevin; Gillingwater, Thomas H.; Parson, Simon H.

In: Annals of Neurology, Vol. 79, No. 2, 02.2016, p. 217-230.

Research output: Contribution to journalArticle

Somers, E, Lees, RD, Hoban, K, Sleigh, JN, Zhou, H, Muntoni, F, Talbot, K, Gillingwater, TH & Parson, SH 2016, 'Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy', Annals of Neurology, vol. 79, no. 2, pp. 217-230. https://doi.org/10.1002/ana.24549
Somers E, Lees RD, Hoban K, Sleigh JN, Zhou H, Muntoni F et al. Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy. Annals of Neurology. 2016 Feb;79(2):217-230. https://doi.org/10.1002/ana.24549
Somers, Eilidh ; Lees, Robert D. ; Hoban, Katie ; Sleigh, James N. ; Zhou, Haiyan ; Muntoni, Francesco ; Talbot, Kevin ; Gillingwater, Thomas H. ; Parson, Simon H. / Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy. In: Annals of Neurology. 2016 ; Vol. 79, No. 2. pp. 217-230.
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abstract = "ObjectiveSpinal 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.MethodsDevelopment 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.ResultsThe 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.InterpretationOur 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",
author = "Eilidh Somers and Lees, {Robert D.} and Katie Hoban and Sleigh, {James N.} and Haiyan Zhou and Francesco Muntoni and Kevin Talbot and Gillingwater, {Thomas H.} and Parson, {Simon H.}",
note = "Acknowledgment S.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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T1 - Vascular Defects and Spinal Cord Hypoxia in Spinal Muscular Atrophy

AU - Somers, Eilidh

AU - Lees, Robert D.

AU - Hoban, Katie

AU - Sleigh, James N.

AU - Zhou, Haiyan

AU - Muntoni, Francesco

AU - Talbot, Kevin

AU - Gillingwater, Thomas H.

AU - Parson, Simon H.

N1 - Acknowledgment S.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.

PY - 2016/2

Y1 - 2016/2

N2 - ObjectiveSpinal 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.MethodsDevelopment 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.ResultsThe 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.InterpretationOur 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

AB - ObjectiveSpinal 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.MethodsDevelopment 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.ResultsThe 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.InterpretationOur 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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VL - 79

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EP - 230

JO - Annals of Neurology

JF - Annals of Neurology

SN - 0364-5134

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ER -