Microvascular pathology may play a greater role than previously known in the etiology of spinal muscular atrophy (SMA), according to a study.

The findings showed that the underlying biological mechanism of microvascular dysfunction is autonomous abnormalities in angiogenesis and blood vessel creation, consequent to survival motor neuron (SMN) deficit in cultured human and mouse endothelial cells. The research on vascular and cellular biomarkers suggests that microvasculopathy is a key component of SMA.

These data were recently published in the Journal of Clinical Investigation.

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“In light of all these findings, our study suggests that therapeutic strategies for SMA should also include the correction of the SMN deficiency in the periphery, including the vascular system,” the authors wrote.

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This experimental study used transgenic mice to evaluate the retinal vascular defect characteristics associated with SMA. The angiogenic phenotype consisted of decreased or even depletion of outgrowth and the number of growing tips in the retinal vascular plexus, along with deficient vessel maturation and unorganized proliferation.

Impaired angiogenesis and blood vessel maturation were the primary mechanisms responsible for these findings. Notably, this pathologic process seems to cease upon administration of the SMN protein.

Moreover, individuals with higher circulating endothelial cell count but lower endothelial progenitor cell count in peripheral blood seem to experience SMA higher on the severity spectrum.

The latter result suggests a potential use of the circulating endothelial vs progenitor cell count ratio as a severity marker that depicts the degree of endothelial injury. Remarkably, even in cultured cells with great severity, these changes also regressed with SMN.

To explain the mechanism through which SMN may play such a determining role in endothelial pathology, the study identified autonomous impairment during angiogenesis in both human and mouse cultured cells in the absence of SMN.

Specifically, endothelial cell migration and vascular tube formation were defective, while apoptosis remained unaffected. These results were later replicated in isolated cells from the aorta of mice with SMA, showcasing similar behavior regarding the vascular tube.

“Future studies on endothelial cell-specific SMN restoration in SMA mice will be needed to better understand the role of endothelial cells in disease pathogenesis and progression, and to what extent that microvasculopathy may contribute to the multiorgan involvement in SMA,” the study authors wrote.


Zhou H, Hong Y, Scoto M et al. Microvasculopathy in SMA is driven by a reversible autonomous endothelial cell defect. J Clin Invest. Published online September 13, 2022. doi:10.1172/jci153430