Blood vessel damage may contribute to nerve cell loss in SMA: Study
Abnormalities found in spinal cord tissue of infants who died from disease
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- Research suggests blood vessel damage and blood-spinal cord barrier breakdown contribute to nerve cell loss in SMA.
- These vascular defects lead to inflammation and motor neuron vulnerability in the spinal cord of SMA patients.
- Monitoring vascular health and developing targeted therapies may improve SMA patient outcomes.
Damage to blood vessels in the spinal cord may play a role in nerve cell loss in spinal muscular atrophy (SMA), a new study suggests.
A detailed examination of spinal cord tissue from infants who died from severe SMA detected abnormalities in the cells that line spinal cord blood vessels, as well as the breakdown of the blood-spinal cord barrier, a protective layer that tightly controls what can pass from the bloodstream into spinal cord tissue.
Together, these defects appeared to trigger signs of inflammation throughout the spinal cord, the data showed.
“Long-term monitoring and therapeutic strategies that consider vascular health may improve outcomes of SMA patients,” researchers wrote.
The study, “Microvascular pathology in the spinal cord of severe spinal muscular atrophy patients,” was published in Acta Neuropathologica Communications.
In most cases, SMA caused by inherited mutations in the SMN1 gene
In most cases of SMA, inherited mutations in the SMN1 gene result in a deficiency of the SMN protein. Motor neurons — the specialized nerve cells that control muscle movement — are particularly sensitive to a lack of SMN, and this drives the hallmark motor symptoms of SMA, such as muscle weakness and wasting.
An SMN deficiency can also affect other cell types, including endothelial cells that line blood vessels. Muscle biopsies from SMA patients across different degrees of disease severity show changes in blood vessel density, number, and structure. Moreover, studies in SMA animal models suggest that vascular defects may also contribute directly to nerve cell degeneration.
“These observations suggest that vascular endothelial dysfunction may contribute both to local spinal cord [disease] and to wider systemic involvement in SMA,” and “highlights the need for focused investigation of the human vascular network in SMA,” wrote a team led by researchers in Scotland.
In this study, the team examined blood vessels in postmortem spinal cord tissue samples from infants who died from severe SMA, ages 1 month to 12 months, and age-matched unaffected controls.
When the researchers stained spinal cord samples to visualize the location of von Willebrand factor (VWF), a marker of endothelial cell health, control blood vessels appeared bright and even, whereas SMA samples showed uneven staining. In the ventral horn of the spinal cord — the area most affected in SMA — the total area stained for VWF was significantly lower. Individual blood vessels in SMA samples also had much less VWF.
Despite these findings, electron microscopy revealed no major differences between SMA and controls in endothelial cell size, cell number, or vessel diameter.
Blood-spinal cord barrier showed signs of breakdown
Upon closer inspection, endothelial cells in SMA samples showed clear signs of damage, whereas control samples appeared healthy. SMA damage included disrupted cell membranes, cell swelling (edema), damaged internal structures, and vacuoles (small empty spaces within cells).
Endothelial cells play a critical role in forming the blood-spinal cord barrier (BSCB). In healthy tissue, these cells form a continuous, tightly connected layer anchored to a structure called the basement membrane.
In SMA, this protective barrier showed signs of breakdown. The researchers observed gaps in the endothelial lining, allowing blood cells to come into abnormal contact with the basement membrane. The basement membrane was also affected, showing detachment from endothelial cells and membrane thickening. None of these abnormalities was seen in control samples.
Our findings indicate that vascular defects may contribute to motor neuron vulnerability and disease progression.
BSCB leakage was also detected in SMA samples. In control samples, two blood proteins — fibrinogen and hemoglobin — that are normally confined to blood vessels, remained inside blood vessels. In contrast, these proteins were detected outside the blood vessels in SMA cases.
“The presence of any fibrinogen leakage from vessels provides clear evidence of BSCB dysfunction in SMA,” the team noted.
When the BSCB breaks down, it can trigger inflammation in the nervous system — particularly by activating local immune cells called microglia. Although the number of microglia was similar between groups, microglia in SMA tissue showed signs of activation compared with those in control samples, which appeared in a resting state.
Nearly all microglia in SMA also expressed CD68, a protein marker of immune activation, whereas none did in control samples. This activated microglial pattern was seen throughout the spinal cord, not just in the ventral horn where motor neurons are lost.
“Our findings indicate that vascular defects may contribute to motor neuron vulnerability and disease progression,” the researchers concluded. “Further studies are warranted to define the contribution of vascular dysfunction to SMA [development] and to assess whether current therapies adequately address this aspect of the disease.”
