Endothelin receptor expression in the normal and injured spinal cord: Potential involvement in injury-induced ischemia and gliosis

The endothelins (ETs) are a family of peptides that exert their biological effects via two distinct receptors, the endothelin A receptor (ET_AR) and the endothelin B receptor (ET_BR). To more clearly define the potential actions of ETs following spinal cord injury, we used immunohistochemistry and confocal microscopy to examine the protein expression of ET_AR and ET_BR in the normal and injured rat spinal cord. In the normal spinal cord, ET_AR immunoreactivity (IR) is expressed by vascular smooth muscle cells and a subpopulation of primary afferent nerve fibers. ET_BR-IR is expressed primarily by radial glia, a small population of gray and white matter astrocytes, ependymal cells, vascular endothelial cells, and to a lesser extent in smooth muscle cells. Fourteen days following compression injury to the spinal cord, there was a significant upregulation in both the immunoexpression and number of astrocytes expressing the ET_BR in both gray and white matter and a near disappearance of ET_BR-IR in ependymal cells and ET_AR-IR in primary afferent fibers. Conversely, the vascular expression of ET_AR and ET_BR did not appear to change. As spinal cord injury has been shown to induce an immediate increase in plasma ET levels and a sustained increase in tissue ET levels, ETs would be expected to induce an initial marked vasoconstriction via activation of vascular ET_AR/ET_BR and then days later a glial hypertrophy via activation of the ET_BR expressed by astrocytes. Strategies aimed at blocking vascular ET_AR/ET_BR and astrocyte ET_BRs following spinal cord injury may reduce the resulting ischemia and astrogliosis and in doing so increase neuronal survival, regeneration, and function.