TY - JOUR
T1 - Microvasculopathy in SMA is driven by a reversible autonomous endothelial cell defect
AU - Zhou, Haiyan
AU - Hong, Ying
AU - Scoto, Mariacristina
AU - Thomson, Alison
AU - Pead, Emma
AU - MacGillivray, Tom
AU - Hernandez-Gerez, Elena
AU - Catapano, Francesco
AU - Meng, Jinghon
AU - Zhang, Qiang
AU - Hunter, Gillian
AU - Shorrock, Hannah
AU - Ng, Thomas
AU - Hamida, Abedallah
AU - Sanson, Mathilde
AU - Baranello, Giovanni
AU - Howell, Kevin
AU - Gillingwater, Thomas H
AU - Brogan, Paul
AU - Thompson, Dorothy A
AU - Parson, Simon H.
AU - Muntoni, Francesco
PY - 2022/9/13
Y1 - 2022/9/13
N2 - Spinal muscular atrophy (SMA) is a neuromuscular disorder due to degeneration of spinal cord motor neurons caused by the 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 unfavourable 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 biomarkers 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.
AB - Spinal muscular atrophy (SMA) is a neuromuscular disorder due to degeneration of spinal cord motor neurons caused by the 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 unfavourable 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 biomarkers 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.
U2 - 10.1172/JCI153430
DO - 10.1172/JCI153430
M3 - Article
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
ER -