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Endothelins reciprocally regulate VEGF‐A and angiopoietin‐1 production in cultured rat astrocytes: Implications on astrocytic proliferation
Author(s) -
Koyama Yutaka,
Maebara Yuko,
Hayashi Mio,
Nagae Ryuji,
Tokuyama Shogo,
Michinaga Shotaro
Publication year - 2012
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.22411
Subject(s) - biology , astrocyte , endocrinology , endothelins , medicine , vascular endothelial growth factor , cyclin d1 , bromodeoxyuridine , endothelin 1 , receptor , cancer research , cell growth , central nervous system , cell cycle , biochemistry , cell , vegf receptors
Vascular endothelial growth factors (VEGFs) and angiopoietins (ANGs) are involved in pathophysiological responses in damaged nerve tissues. Astrocytes produce VEGFs and ANGs upon brain ischemia and traumatic injury. To clarify the extracellular signals regulating VEGF and ANG production, effects of endothelins (ETs), a family of endothelium‐derived peptides, were examined in cultured rat astrocytes. ET‐1 (100 nM) and Ala 1,3,11,15 ‐ET‐1 (100 nM), an ET B receptor agonist, increased VEGF‐A mRNA levels in cultured astrocytes, while ANG‐1 mRNA was decreased by ETs. ET‐1 did not affect astrocytic VEGF‐B, placental growth factor (PLGF), and ANG‐2 mRNA levels. The effects of ET‐1 on VEGF‐A and ANG‐1 mRNAs were inhibited by BQ788, an ET B antagonist. Release of VEGF‐A proteins from cultured astrocytes was increased by ET‐1. In contrast, ET‐1 reduced release of astrocytic ANG‐1. Exogenous ET‐1 (100 nM) and VEGF 165 (100 ng/mL), an isopeptide of VEGF‐A, stimulated bromodeoxyuridine (BrdU) incorporation into cultured astrocytes. Treatment with ET‐1 and VEGF 165 increased the numbers of cyclin D1‐positive astrocytes. Exogenous ANG‐1 (250 ng/mL) did not stimulate the BrdU incorporation. Increases in BrdU incorporation by ET‐1 and VEGF 165 were not affected by ANG‐1. In 60–70% confluent cultures, SU4312 (10 μM), a VEGF receptor tyrosine kinase inhibitor, partially reduced the effects of ET‐1 on BrdU incorporation and cyclin D1 expression. ET‐induced BrdU incorporation and cyclin D1 expression were reduced by a neutralizing antibody against VEGF‐A. Our findings suggest that ET‐1 is a factor regulating astrocytic VEGF‐A and ANG‐1, and that increased VEGF‐A production potentiates ET‐induced astrocytic proliferation by an autocrine mechanism. © 2012 Wiley Periodicals, Inc.