Microvasculopathy in spinal muscular atrophy is driven by a reversible autonomous endothelial cell defect
Haiyan Zhou, … , Simon H. Parson, Francesco Muntoni
Haiyan Zhou, … , Simon H. Parson, Francesco Muntoni
Published September 13, 2022
Citation Information: J Clin Invest. 2022;132(21):e153430. https://doi.org/10.1172/JCI153430.
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Research Article Neuroscience

Microvasculopathy in spinal muscular atrophy is driven by a reversible autonomous endothelial cell defect

Abstract

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.

Authors

Haiyan Zhou, 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 K. Ng, Abedallah Hamida, Mathilde Sanson, Giovanni Baranello, Kevin Howell, Thomas H. Gillingwater, Paul Brogan, Dorothy A. Thompson, Simon H. Parson, Francesco Muntoni

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Figure 3

SMN restoration with antisense treatment restores retinal vasculature in SMA mice.

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SMN restoration with antisense treatment restores retinal vasculature in...
(A) The full-length SMN2 transcripts and truncated SMN2 transcripts without exon 7 (Δ7 SMN2) were measured by quantitative real-time PCR in retinas collected from PMO25-treated SMA mice (SMA+PMO25, n = 7), compared with saline-treated SMA mice (n = 5). (B) Representative image of Western blotting and semiquantification of SMN protein expression in mouse retinas from SMA mice after PMO25 treatment (n = 6), compared with saline-treated SMA controls (n = 5). Mouse GAPDH protein was used as a loading control. (C) Mouse retinas from saline-treated SMA, PMO25-treated SMA, and healthy littermate controls were stained with GSL I/IB4 lectin (green) to indicate blood vessels of the primary vascular plexus. (D) The vascular plexus was quantified using AngioTool on vessel outgrowth, endpoints, and lacunarity in mouse retinas from saline-treated SMA, PMO25-treated SMA, and healthy littermate control mice. One-way ANOVA with Tukey’s post hoc test was used for data analysis. Data represent mean ± SEM, with individual data points displayed. N ≥ 3 eyes from at least 3 mice for each group. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Scale bar: 400 μm in low-power images and 200 μm in high-power inset images.