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 4

Depletion of neuronal components and increased microgliosis in SMA mouse retina.

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Depletion of neuronal components and increased microgliosis in SMA mouse...
(A) Gross appearance of H&E-stained retina from SMA and healthy control mice at P5 and P8. GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; NF, nerve fiber; ONL, outer nuclear layer; OPL, outer plexiform layer; OS, outer segment. (B) Quantification of retinal thickness in sections from H&E staining. (C) Retinal ganglion cells (RGCs) stained with BRN3a (green), with nuclei in blue. The insets show high-power fields of the RGC layer. (D) Quantification of RGCs per unit area (PUA) at P5 and P8. (E) Horizontal and amacrine cells were stained with PAX6 transcription factor (red), with nuclei in blue. (F) Quantification of horizontal and amacrine cells PUA at P8. (G) Microglia, stained with GSL I/IB4 isolectin, differentiated from blood vessels by their morphology. Images were taken from the retinal periphery at P8. (H) Quantification of microglia PUA at P5 and P8. (I) Light-sensitive photoreceptors: red/green and blue opsin identified rods (green) and rhodopsin identified cones (red), with nuclei in blue. (J) Relative quantification of rod and cone signals at P8. All representative images were taken at P8, except where indicated at P5. Scale bars: 100 μm in A; 50 μm in low-power images and 25 μm in high-power inset images in C; 25 μm in E; 50 μm in G; 25 μm in I. B, D, and H were analyzed by 1-way ANOVA with Tukey’s post hoc test; F and J were analyzed by unpaired 2-tailed Student’s t test. The field of view (area) for assessment of cell density was 6,250 μm2. 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.