Microvasculopathy in spinal muscular atrophy: The endothelium as a target of SMN deficiency and an amplifier of disease.

Spinal muscular atrophy (SMA) is caused by deficiency of the ubiquitous survival motor neuron (SMN) protein. Degeneration of anterior horn motor neurons defines the disease, but many organs are affected, including heart, liver, kidney, and bone. The vascular compartment is among them: digital necrosis in infants with the fewest SMN2 copies, capillary rarefaction in SMA mice, and decreased von Willebrand factor with fibrinogen extravasation in human post-mortem spinal cord. Whether these reflect endothelial injury by SMN deficiency itself or capillary adaptation to atrophic, denervated tissue has not been examined systematically. SMN-depleted endothelial cells form defective networks and migrate poorly in neuron-free systems, but this is based on a single unreplicated study in macrovascular and progenitor cells, which do not recapitulate human spinal cord microvascular endothelium. Ventral horn hypoxia precedes or accompanies weakness, retinal vessels fail before ganglion cells are lost, but retinal networks and patient-derived endothelial progenitors recover when SMN is restored. Demand-matched regression, reduced cardiac output, post-mortem artefact, critical illness, autonomic dysfunction and measurement confounding account for part of the phenotype, not all. Throughout, we keep vascular abnormality distinct from impaired perfusion, demonstrated only in mice. SMN has never been deleted from, or restored in, the endothelium alone in vivo. We therefore hypothesise, as a falsifiable model, not a proven mechanism, that the endothelium is injured cell-autonomously alongside other SMN-dependent lineages and amplifies rather than initiates disease, and we outline the genetic experiments required to falsify it. Retinal angiography and capillaroscopy are accessible readouts, neither visualising the cord.