Neurovascular unit remodeling in cervical spondylotic myelopathy

Abstract

Cervical spondylotic myelopathy (CSM), the most common cervical spinal cord disorder in elderly population, has posed great health and economic burdens worldwide. Surgical decompression to the compressive cord is still the mainstay of treatment strategy. However, the surgical efficacy varies, some patients could obtain partial function recovery, others undergo neurological deterioration, even remain lifelong irreversibly disabled. Hence, there is great urgency to fully elucidate the pathophysiological mechanism of CSM and neurorestoration after surgical decompression. Neurovascular unit (NVU) damage has been preferentially implicated in the pathophysiological mechanism of CNS disorders, implicating crucial neurorestorative potential for translational research. In this study, we systematically explore the primary characteristics of NVU and the pathophysiological mechanism of NVU remodeling and neuronal/axonal plasticity in an experimental CSM model. Firstly, TEM was used to explore the ultrastructural characteristics of NVU in CSM model. The key characteristics include: neuronal degeneration and apoptosis; disruption of axonal cytoskeleton (neurofilaments), myelin sheath and dystrophy of axonal terminal with dysfunction mitochondria; activated astrocytes and microglia, and degenerative oligodendrocytes; swollen microvascular endothelium and loss of tight junction integrity; corrosive basement membrane and collapsed microvascular wall; proliferated pericytes and perivascular astrocytic endfeet. Hence, NVU destruction is one of the most crucial pathological mechanisms for CSM. Secondly, to explore the endogenous potential of neurorestoration, we investigated the compensatory changes in the adjacent level to the compressive epicenter. We found evident increased microvascular area with wrapping proliferated astrocytic endfeet, restoration of blood spinal cord barrier (BSCB) permeability, neuronal surviving and synaptic plasticity, as well as spontaneous functional recovery. Thus, NVU compensatory change, in particular in adjacent level, is one of the most essential pathomechanisms of spontaneous recovery in CSM. Thirdly, in order to determine whether NVU remodeling attributes to neurorestoration after surgical decompression, we used the model to simulate surgical decompression in CSM patient. The characteristics of NVU remodeling mainly include: hyperplastic microvascular wall with increased expression of tight junction protein and restoration of endothelial barrier; proliferated pericyte process, reactive astrocytes and perivascular astrocytic endfeet; promoted neuron survival with rich organelles, neurofilament re-arrangement and axonal remyelination, synaptic plasticity with mitochondrial remodeling. In brief, NVU remodeling is one critical pathophysiological mechanism for neurorestoration and functional recovery for surgical decompression. We further explored the dynamics of mitophagy in compressive and decompression condition. Surgical decompression promoted neuronal and axonal (synaptic) plasticity with functional recovery, which may attribute to alleviating accumulation of (non-) phosphorylated NFH in neuron and axon. Autolysosomes, mitolysosomes and autophagic flux promoted after compression, while surgical decompression inhibited the process. The neuroplasticity may attribute to alleviating excessive mitophagy and mitochondrial plasticity associated with microcirculation improvement after decompression. The overreactive mitophagy may be regulated by PINK1-PARKIN pathway, whereas decompression inhibits the process. These results suggested that PINK1-PARKIN pathway may play an important role in modulating mitochondrial plasticity and thus promotes neuroplasticity after surgical decompression. In conclusion, NVU destruction may be one critical pathophysiological mechanism for CSM, surgical decompression could promote NVU remodeling and thereby neuronal and axonal (synaptic) plasticity, which may be regulated by PINK1-PARKIN mediated mitophagy.