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

Abstract

Abstract. The receptors for endothelins (ETs) are classified into the ET A and ET B types. ET B 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 ET B receptors in the brain are reviewed. The administration of ET B agonists and antagonists in nerve injury models showed that several astrocytic functions are regulated by ET B receptors. The activation of ET B 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 ET B receptors. In brain insults and neurodegenerative diseases, these functions of astrocytes affect the protection and repair of damaged nerve tissues. Thus, astrocytic ET B receptors could be a target for novel types of neuroprotective drugs.

Overactivation of corticotropin-releasing factor receptor type 1 and aquaporin-4 by hypoxia induces cerebral edema

“…ET-1 receptors (A and B) are widely expressed in the endothelial cells of the cerebral microvasculature as well as in populations of neurons, astrocytes and microglia, and ET-1 is thought to mediate interactions between astrocytes and the cerebral microvasculature (31,32) that have an important role in ischemia or stroke-induced brain edema and injury (31). Ischemia induces upregulation of expression of ET-1/3 and its receptors-A/B in the rat cortex (33), and activation of ET-1 by ischemia induces brain edema via AQP4 in rat astrocytic end-feet (34).…”

“…In humans, ET-1 levels >5.5 fmol/mL in serum are linked to severe brain edema in acute stroke patients (35). ET-1 A plays a protective role during brain edema (36), but ET-1 B receptors also regulate astrocytic function (31); in an experimental rat model of stroke, an ET-1 B antagonist could reduce brain edema, serum ET-1, and astrocyte swelling (37). Recently, ET-1 has been shown to promote NO production and astrocyte migration by activation of ET-1 B and NF-κB, inducing iNOS (38).…”

Glial regulation of the blood-brain barrier in health and disease

“…Depending on the type and severity of disturbance in the CNS, astrocytes can undergo both lossof-function (e.g., failure of glutamate uptake [117,121]) and/ or gain-of-function (production of a wide range of molecules including cytokines [122][123][124]). These changes cannot only regulate CNS vasculature remodeling but also cause activation of infiltrating immune cells and/or induce changes in neurons and oligodendrocytes [2,[125][126][127]. In the following section, we will discuss the regulation of the BBB by reactive astrocytes in the context of the neuroinflammatory disease multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE).…”

Notch1–STAT3–ETB R signaling axis controls reactive astrocyte proliferation after brain injury

“…In contrast, we found Jagged1/Notch1 signaling could promote ETB R expression indirectly by increasing p-STAT3. Importantly, most CNS injuries result in the local release of ET-1-and ETB R -mediated signaling as well as the secretion of growth factors/cytokines with signals transduced by STAT3 (28). After brain injury, ET-1, EGF, and IL-6 are released by several different cell types, including reactive astrocytes, and act in an autocrine/paracrine manner (29).…”