Microvasculopathy in SMA is driven by a reversible autonomous endothelial cell defect

Haiyan Zhou* (Corresponding Author), Ying Hong, Mariacristina Scoto, Alison Thomson, Emma Pead, Tom MacGillivray, Elena Hernandez Gerez, Francesco Catapano, Jinhong Meng, Qiang Zhang, Gillian Hunter, Hannah K. Shorrock, Thomas Ng, Abedallah Mahmod Shehda Hamida, Mathilde Sanson, Giovanni Baranello, Kevin Howell, Thomas H. Gillingwater, Paul Brogan, Dorothy Thompson* (Corresponding Author)Simon Parson* (Corresponding Author), Francesco Muntoni* (Corresponding Author)

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)


Spinal muscular atrophy (SMA) is a neuromuscular disorder due to degeneration of spinal cord motor neurons caused by deficiency of the ubiquitously expressed SMN protein. Here, we present a retinal vascular defect in patients, recapitulated in SMA transgenic mice, driven by failure of angiogenesis and maturation of blood vessels. Importantly, the retinal vascular phenotype was rescued by early, systemic SMN restoration therapy in SMA mice. We also demonstrate in patients an unfavorable imbalance between endothelial injury and repair, as indicated by increased circulating endothelial cell counts and decreased endothelial progenitor cell counts in blood circulation. The cellular markers of endothelial injury were associated with disease severity and improved following SMN restoration treatment in cultured endothelial cells from patients. Finally, we demonstrated autonomous defects in angiogenesis and blood vessel formation, secondary to SMN deficiency in cultured human and mouse endothelial cells, as the underlying cellular mechanism of microvascular pathology. Our cellular and vascular biomarker findings indicate microvasculopathy as a fundamental feature of SMA. Our findings provide mechanistic insights into previously described SMA microvascular complications, and highlight the functional role of SMN in the periphery, including the vascular system, where deficiency of SMN can be addressed by systemic SMN-restoring treatment
Original languageEnglish
Article numbere153430
Number of pages15
JournalJournal of Clinical Investigation
Issue number21
Early online date13 Sept 2022
Publication statusPublished - 1 Nov 2022

Bibliographical note

We would like to thank Professor Peter Carmeliet at University of Leuven for help with initial mouse retina dissection and staining, Prof Martin Collinson at University of Aberdeen for assistance in staining cells in mouse retinas and Professor Jennifer E. Morgan at University College London for overseeing experiments in mice. This study was supported in part by research funding from the Great Ormond Street Hospital Charity to FM and PB (Reference V0216), Wellcome Trust grant to HZ (Reference 204841/Z/16/Z), UK SMA Trust to FM and MS, SMA Europe grants to FM, THG and SHP, and Anatomical Society PhD
Studentship to SHP. Financial support from the National Institute for Health Research (NIHR) Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London to FM and HZ is acknowledged. The views expressed are those of the authors and not necessarily those of the UK National Health Service (NHS), the NIHR, or the Department of Health. The supports of the MRC Neuromuscular Centre at UCL and of the Muscular Dystrophy UK to the Dubowitz Neuromuscular Centre are also acknowledged.


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