Figure 1.

Vascular relationships within the peripheral nerve compartments and the blood-nerve barrier (A). Vasa nervorum comprise an intrinsic plexus of anastomosing arterioles and capillaries that have both nutritional and functional duties for the nerve. They originate from the main artery (1) accompanying the nerve and provide radicular branches entering the nerve by perforating the epineurium. The epineurial arterioles (2) are longitudinally aligned in between nerve fascicles, and in the deeper epineurial regions they provide anastomotic connections to the perineurial capillaries (3), and subsequently endoneurial capillaries (4). The perineurial and endoneurial vessels establish a capillary network that acts in unison in maintaining a balanced hydrostatic pressure of the fluid within the endoneurium The adjacent endothelial cells of the perineurial and endoneurial capillaries are firmly connected with each other via tight junction molecules, and their basement membrane is nonfenestrated, thereby forming tight and highly regulated interfaces at which the nerve interacts with the systemic circulation. Hence, both of these perineurial and endoneurial interfaces represent structural and functional continuum—the blood-nerve barrier. Conversely, the arterioles of the epineurium exhibit open endothelial clefts and fenestrated basement membrane, therefore they are considered “leaky” to varieties of substances and tracers. The perineurium (B) is the sheath surrounding the axons and extends between the basement membranes of the perineurial capillaries and the endoneuria. It includes multiple concentric layers of perineurial fibroblasts combined with a dense network of collagen fibrils that surround each endoneurium. The perineurium provides the peripheral nerve structural integrity and protection against the mechanical hazards. The perineurial fibroblasts, particularly in the innermost layers, are connected with tight junctions and therefore provide a selective diffusion barrier. The perineurial blood-nerve interface is most apparent in the transperineurial vessels which connect with the endoneurial capillaries. The endoneurium (C) extends between the endoneurial capillaries and the myelin surrounding the axons. The microenvironment of the endoneurium is highly regulated, and its homeostasis maintained by both perineural and endoneurial cells. This includes the hydrostatic pressure of the endoneurial fluid, its electrolytes, albumin, nutrients, and selective cell types. The normal cellularity of the endoneurium is sparse, and consists of pericytes, mast cells, and occasional lymphocytes; whereas on the axons within layers of the myelin, the myelinating Schwann cells, and sporadically the nonmyelinating Schwann cells, are present. The endoneurium directly interfaces with the axons at the nodes of Ranvier. (A, axon; E, endothelial cell; BM, basement membrane; PC, perineurial cells; M, myelin; S, myelinating Schwann cell; P, pericyte; L, lymphocyte; MC, mast cell; NS, nonmyelinating Schwann cell; NR, node of Ranvier).