Early disruption of neurovascular units and microcirculatory dysfunction in the spinal cord in spinal muscular atrophy type I.

Spinal muscular atrophy type I (SMA-I) is characterized by progressive muscle weakness with onset in early infancy, usually resulting in mortality before two years of age. However, the processes underlying the pathophysiological progression of the disease remain unclear. Prior to the onset of muscle weakness, a regression of local capillaries is observed along with motor neuron loss. Local populations of neurons, astrocytes, and vascular endothelial cells constitute a neurovascular unit (NVU), in which neuronal and synaptic metabolism is tightly coupled to capillary blood flow by astrocyte-mediated vasodilatory control. We hypothesize that survival motor neuron protein deficiency and initial neuronal dysfunction leads to the regression of vascular beds and the disruption of NVU function. As a result, local capillary blood flow becomes insufficient, leading to metabolic stress in neurons, endothelial cells, pericytes, and astrocytes, ultimately disrupting the astrocytic regulation of capillaries. This pathogenic process may accelerate the loss of anterior horn motor neurons, leading to the further regression of capillaries and astroglial dysfunction. Hypocapnia, resulting from dehydration and hyperventilation during therapeutic manual ventilation, might further damage the NVU. Moreover, disruption of the microcirculation may affect sympathetic and sensory neurons in the spinal cord, contributing to sympathetic hyperactivity and sensory nerve degeneration, respectively. These mutually reinforcing processes may underlie the progression of muscle weakness during infancy in SMA-I. Therefore, disruption of the NVU and a stressful neurovascular environment in the anterior horn may play important roles in disease initiation and/or progression in SMA-I. The NVU is therefore a critical therapeutic target for treating SMA-I. Our hypothetical model may provide insight into why most neuroprotective strategies that do not address astroglial and vascular cell dysfunction have limited efficacy.