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.
View: Text | PDF
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

×

Figure 5

Increased vascular injury and decreased vascular repair revealed in peripheral blood from SMA patients.

Options: View larger image (or click on image) Download as PowerPoint
Increased vascular injury and decreased vascular repair revealed in peri...
(A) Levels of CECs (number/mL) in peripheral blood from SMA patients (including type 1, 2, and 3, n = 32) and healthy controls (n = 17). (B) Comparison of CEC counts between healthy control (n = 17) and SMA type 1 (n = 6), type 2 (n = 12), and type 3 (n = 11). (C) Correlation between CEC counts and the copy number of SMN2 gene in SMA patients (r2 = 0.2344, P < 0.05). (D) Comparison of EPC-CFU numbers in peripheral blood from SMA patients (including type 1, 2, and 3, n = 28) and healthy controls (n = 13). (E) Comparison of EPC-CFU numbers between healthy controls and SMA type 1 (n = 7), type 2 (n = 11), and type 3 (n = 8). (F) Correlation between numbers of EPC-CFUs and SMN2 copy (r2 = 0.1696, P = 0.1435). (G) Comparison of numbers of EPC-CFUs from healthy controls (n = 13), SMA type 1 patients (SMA-I, n = 5), EPCs isolated from SMA type 1 and treated with scrambled Vivo-Morpholino (SMA-I+Scr-VMO, n = 5), and EPCs isolated from SMA type 1 and treated with therapeutic AON (SMA-I+VMO25, n = 5). A and D were analyzed by unpaired 2-tailed Student’s t test; B, E, and G were analyzed by 1-way ANOVA with Tukey’s post hoc test; C and F were analyzed by Spearman’s rank correlation coefficient for associations of CECs and EPCs with SMN2 copy numbers. Data represent mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.