Role of the astrocytic ET_B receptor in the regulation of extracellular endothelin‐1 during hypoxia

Abstract

Astrocytes are known to possess an effective endothelin (ET) eliminatory system which involves astrocytic ET(A) and ET(B) receptors and may become particularly relevant under pathophysiological conditions. The present study has therefore been designed to explore the effect of standardized hypoxia on extracellular concentrations of endothelin-1 (ET-1) and on endothelin-converting enzyme (ECE) activity in primary rat astrocytes genetically (sl/sl) or experimentally (dexamethasone) deficient in ET(B) receptors. The results revealed (1) a hypoxia-mediated decrease of extracellular ET-1 in wildtype astrocytes (+/+) that was not observed in ET(B)-deficient (sl/sl) cultures; (2) an ET receptor antagonist-induced increase in ET-1 in the media of both genotypes with further elevation upon hypoxia in +/+ cultures only; (3) augmentation of the dexamethasone-induced increase in extracellular ET-1 by hypoxia in +/+, but not in sl/sl cultures; (4) synergistic reduction of ET(B) gene transcription by hypoxia and dexamethasone; and (5) significant increases in endothelin-converting enzyme activity in the presence of hypoxia. To conclude, hypoxia stimulates astrocytic release of mature ET-1. This stimulation is (over)compensated for by increased ET-1 binding to functional ET(B) receptors. ET(B) deficiency, whether genetic or experimentally induced, impairs elimination of extracellular ET-1.

Endothelin-1 Regulates Astrocyte Proliferation and Reactive Gliosis via a JNK/c-Jun Signaling Pathway

“…Endothelin-1 (ET-1) is implicated in many CNS pathologies that involve reactive gliosis (Jiang et al, 1993;Yamashita et al, 1994;Zhang et al, 1994;Nie and Olsson, 1996;Stiles et al, 1997;Baba, 1998;Hasselblatt et al, 2001Hasselblatt et al, , 2003Egnaczyk et al, 2003;Sofroniew, 2005). Expression of ET-1 and its receptors (ET-Rs) is strongly upregulated in astrocytes after brain injury (Jiang et al, 1993;Zhang et al, 1994;Hino et al, 1996;Nie and Olsson, 1996;Rogers et al, 1997;Sakurai-Yamashita et al, 1997;Baba, 1998).…”

“…Expression of ET-1 and its receptors (ET-Rs) is strongly upregulated in astrocytes after brain injury (Jiang et al, 1993;Zhang et al, 1994;Hino et al, 1996;Nie and Olsson, 1996;Rogers et al, 1997;Sakurai-Yamashita et al, 1997;Baba, 1998). Astrocytes are autocrine targets of ET-1 action, which results in increased cell proliferation (Lazarini et al, 1996;Hasselblatt et al, 2001Hasselblatt et al, , 2003Rogers et al, 2003;Desai et al, 2004). A direct role for ET-1 in reactive gliosis was demonstrated by in vivo infusion of exogenous ETs or ET-R agonists, which caused astrocyte hypertrophy and proliferation .…”

ET-1 induces cortical spreading depression via activation of the ETAreceptor/phospholipase C pathway in vivo

“…Several studies have shown that ET-1 affects numerous cell functions of cultured astrocytes such as control of ion channel activity (5), glutamate efflux (52) and uptake (41), glucose utilization (58), permeability of gap junction communications (3, 16), and calcium signaling (3, 64). In turn, astrocytes are a major source of ET-1 (12, 13) and seem to play an important role in the regulation of ET-1 levels within the CNS (14,24,25).In contrast to the cerebrovascular system, in which ET A receptors are the major receptor subtype, astrocytes predominantly express the ET B receptor subtype (26,38). However, at least in cultured astrocytes, there has also been evidence of ET A receptor mRNA expression (13) and an ET A /ET B hybrid receptor has been postulated (31).…”

“…Several studies have shown that ET-1 affects numerous cell functions of cultured astrocytes such as control of ion channel activity (5), glutamate efflux (52) and uptake (41), glucose utilization (58), permeability of gap junction communications (3,16), and calcium signaling (3,64). In turn, astrocytes are a major source of ET-1 (12,13) and seem to play an important role in the regulation of ET-1 levels within the CNS (14,24,25).…”

À quoi sert le système endothéline ?

“…Il a été montré in vitro que la leptine induisait une stimulation de la synthèse et de la sécrétion d'ET-1 à partir de cultures primaires de cellules endothéliales [16]. Une inhibition de la production d'ET-1 par les astrocytes soumis à une hypoxie, associée à une augmentation d'activité ECE-1 à été mise en évidence [17]; cette inhibition n'est pas retrouvée dans les cultures d'astrocytes issus d'animaux invalidés pour le gène ET-B. Dans les cellules endothéliales cultivées en hypoxie, les facteurs AP-1 (activating protein-1), GATA-2 et NF-1 (nuclear factor-1) sont impliqués dans la stabilisation de la liaison du facteur HIF-1 (hypoxia-inducible factor-1) sur le promoteur d'ET-1 en induisant le recrutement de la protéine p300/CBP (CREB binding protein) [18].…”