Endothelin systems in the brain: involvement in pathophysiological responses of damaged nerve tissues

Abstract

In addition to their potent vasoconstriction effects, endothelins (ETs) show multiple actions in various tissues including the brain. The brain contains high levels of ETs, and their production is stimulated in many brain disorders. Accumulating evidence indicates that activation of brain ET receptors is involved in several pathophysiological responses in damaged brains. In this article, the roles of brain ET systems in relation to brain disorders are reviewed. In the acute phase of stroke, prolonged vasospasm of cerebral arteries and brain edema occur, both of which aggravate brain damage. Studies using ET antagonists show that activation of ETA receptors in the brain vascular smooth muscle induces vasospasm after stroke. Brain edema is induced by increased activity of vascular permeability factors, such as vascular endothelial growth factor and matrix metalloproteinases. Activation of ETB receptors stimulates astrocytic production of these permeability factors. Increases in reactive astrocytes are observed in neurodegenerative diseases and in the chronic phase of stroke, where they facilitate the repair of damaged nerve tissues by releasing neurotrophic factors. ETs promote the induction of reactive astrocytes through ETB receptors. ETs also stimulate the production of astrocytic neurotrophic factors. Recent studies have shown high expression of ETB receptors in neural progenitors. Activation of ETB receptors in neural progenitors promotes their proliferation and migration, suggesting roles for ETB receptors in neurogenesis. Much effort has been invested in the pursuit of novel drugs to induce protection or repair of damaged nerve tissues. From these studies, the pharmacological significance of brain ET systems as a possible target of neuroprotective drugs is anticipated.

Endothelin‐1 increases the expression of VEGF‐R1/Flt‐1 receptors in rat cultured astrocytes through ETB receptors

“…), astrocytes are a likely target for brain ET‐1. Activation of ET B receptors is involved in regulations of several astrocytic pathophysiological responses to brain damage (Koyama and Michinaga ; Koyama ). Thus, the ET‐induced VEGF‐R1 receptor expressions in cultured astrocytes suggest that ET‐1 is a factor‐stimulating astrocytic VEGF‐R1 receptor expression after brain injuries.…”

“…Administrations of an ET B agonist into rat brain increased the number of reactive astrocytes (Ishikawa et al 1997;Koyama et al 2003), while in animal brain injury models, ET B antagonists reduced astrocytic proliferation in damaged areas (Koyama et al 1999;Gadea et al 2008). Further examinations showed that activation of ET B receptors stimulated functional alterations of astrocytes, which included the conversion to reactive astrocytes, and the associated proliferation, morphological changes, and productions of bioactive substances Koyama 2013). From these findings, ETs may serve as regulators of astrocytic pathophysiological responses in damaged brains.…”

“…). Further examinations showed that activation of ET B receptors stimulated functional alterations of astrocytes, which included the conversion to reactive astrocytes, and the associated proliferation, morphological changes, and productions of bioactive substances (Koyama and Michinaga ; Koyama ). From these findings, ETs may serve as regulators of astrocytic pathophysiological responses in damaged brains.…”

Dexamethasone Downregulates Endothelin Receptors and Reduces Endothelin-Induced Production of Matrix Metalloproteinases in Cultured Rat Astrocytes

“…Considering the effects of Dex on ET receptors, the selective reduction of ET signals might be caused by the downregulation of ET receptors. Because the stimulation of either ET A or ET B receptors activated PKC/ERK signals through Gq protein (Koyama, 2013), both ET receptor types are involved in ET-induced MMP production. However, the levels of ET B receptors in cultured astrocytes were much higher than those of ET A receptors (Table 1).…”

X-ray structures of human ETBreceptor provide mechanistic insight into receptor activation and partial activation

“…The human brain contains the highest density of endothelin receptors, with the ETB receptor comprising about 90% in areas such as the cerebral cortex 10 . The ETB receptor in neurons and astrocytes has been implicated in the promotion of neuroprotection, including neuronal survival and reduced apoptosis 11,12 . Moreover, the ET-3/ETB signaling pathway has distinct physiological roles, as compared to the ET-1 pathway.…”