Regulations of Astrocytic Functions by Endothelins: Roles in the Pathophysiological Responses of Damaged Brains

The receptors for endothelins (ETs) are classified into the ETA and ETB types. ETB receptors are highly expressed in astrocytes, but pharmacological usages of this receptor are not clarified. In this article, recent studies on the pathophysiological roles of astrocytic ETB receptors in the brain are reviewed. The administration of ETB agonists and antagonists in nerve injury models showed that several astrocytic functions are regulated by ETB receptors. The activation of ETB receptors causes morphological alterations and proliferation of cultured astrocytes. Astrocytes produce various bio-active substances that can affect damage to nerve tissues. ETs stimulate the production of neurotrophic factors by astrocytes. This action improves impaired brain functions. On the other hand, the production of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF), which induce brain edema, also are stimulated by ETs. These findings indicate that astrocytic functions are effectively regulated by modulations of ETB receptors. In brain insults and neurodegenerative diseases, these functions of astrocytes affect the protection and repair of damaged nerve tissues. Thus, astrocytic ETB receptors could be a target for novel types of neuroprotective drugs.