The neurovascular unit in healthy and injured spinal cord

Abstract

The neurovascular unit (NVU) reflects the close temporal and spatial link between neurons and blood vessels. However, the understanding of the NVU in the spinal cord is far from clear and largely based on generalized knowledge obtained from the brain. Herein, we review the present knowledge of the NVU and highlight candidate approaches to investigate the NVU, particularly focusing on the spinal cord. Several unique features maintain the highly regulated microenvironment in the NVU. Autoregulation and neurovascular coupling ensure regional blood flow meets the metabolic demand according to the blood supply or local neural activation. The blood-central nervous system barrier partitions the circulating blood from neural parenchyma and facilitates the selective exchange of substances. Furthermore, we discuss spinal cord injury (SCI) as a common injury from the perspective of NVU dysfunction. Hopefully, this review will help expand the understanding of the NVU in the spinal cord and inspire new insights into SCI.

Keywords: Blood–spinal cord barrier; neurovascular coupling; neurovascular unit; spinal cord; spinal cord injury.

Figure 1.

The typical components of the neurovascular unit (NVU) in the central nervous system (CNS). The NVU comprises (1) vascular cells, including endothelial cells (ECs) and mural cells, such as pericytes on capillaries and venules, or smooth muscle cells (SMCs) on arterioles and small arteries; (2) neuroglial cells, such as astrocytes; and (3) neurons. ECs form the luminal layer of the vessel wall. The space between adjacent ECs is held by paracellular junctions. The expression of some junctional proteins (including claudin-11, ZO-1, occludin, catenin, and VE-cadherin) is lower in the BSCB than in the BBB. At the arteriolar level (left inset), the basement membrane (BM) and SMC envelope endothelium. Astrocytic endfeet insert into the BM to regulate SMCs through the pia and the glia limitans. The capillary and venule (right inset) lack SMCs, where pericytes embed in the BM and wrap around the ECs on the abluminal side. The astrocytic endfeet attach to the pericytes at both venules and capillaries. Pericyte coverage is less on the BSCB than on the BBB. SMCs, pericytes, and astrocytes all receive neuronal innervation to control their function. In addition, these conformations of cells are also the major cellular structure of the blood–central nervous system barrier.

Figure 2.

A dorsal view of the vascular anatomy of the spinal cord. The spinal cord is supplied by a net-like anastomosing vascular system from the branches of longitudinal anastomotic trunks: one anterior spinal artery and two posterolateral spinal arteries. The pattern of venous return is often parallel to the anatomic arteries. The spinal arteries are supplied by the aorta and lack the siphon structure as in the brain to attenuate cardiac pulsatile blood flow variation. The blood flow direction can change in the median spinal vessels and vasocoronas due to multiple traffic branches. Theoretically, there is a dead point where the opposing pressures stop the blood flow. The location of the dead point is constantly changing due to physical activity or blood pressure fluctuation, indicating that autoregulation in the spinal cord is more sophisticated than in the brain.

Figure 3.

Simplified schematic diagram of the major pathways that regulate blood flow in the cerebral NVU. Neuronal presynaptic release of glutamate (Glu) is taken up by astrocytic processes and acts on metabotropic glutamate receptors (mGluR) to raise [Ca²⁺], inducing the generation of arachidonic acid (AA) from phospholipase A2 (PLA2). The ionotropic glutamate receptors seem less important in controlling blood flow in the spinal cord, and this signaling is not shown in the figure. AA can be converted to multiple prostaglandins (PGs) (by cyclooxygenase, COX), epoxyeicosatrienoic acid (EET) (by cytochrome P450 epoxygenase, CYP450) to dilate vessels, or 20-hydroxyeicosatetraenoic acid (20-HETE) (by ω-hydroxylase, CYP4A) to constrict vessels. Raised [Ca²⁺] in astrocyte endfeet may activate Ca²⁺-gated K⁺ channels (K_Ca) to release K⁺ and activate inward rectifier K⁺ channels (KIRs) on SMCs. The metabolic process of neurons releases adenosine triphosphate (ATP) acting on metabotropic purinergic receptors (P2XR or P2YR) on astrocytes to increase intracellular Ca²⁺. The metabolic byproducts adenosine (to adenosine 2 receptor, A2R) and lactate activate ATP-sensitive potassium (K_ATP) channels, causing vessel relaxation; lactate inhibits PG transporters to cause PG accumulation or activate endothelial nitric oxide synthase (NOS) to release nitric oxide (NO), subsequently causing vasodilation. Neurons release diverse vasoactive neurotransmitters to control the NVU directly, such as vasoactive intestinal peptide (VIP) (to VIP receptor, VIPR), acetylcholine (ACh) (to muscarinic acetylcholine receptor, mAChR), dopamine (to dopamine receptor, DR), norepinephrine (to α-adrenoceptor, α-R), and NO (to cyclic guanosine monophosphate, cGMP).