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J Biol Chem, Vol. 275, Issue 18, 13802-13811, May 5, 2000
From The Wenner-Gren Institute, The Arrhenius Laboratories F3,
Stockholm University, SE-106 91 Stockholm, Sweden
To identify the signaling pathway that mediates
the adrenergic stimulation of the expression of the gene for vascular
endothelial growth factor (VEGF) during physiologically induced
angiogenesis, we examined mouse brown adipocytes in primary culture.
The endogenous adrenergic neurotransmitter norepinephrine (NE) induced
VEGF expression 3-fold, in a dose- and time-dependent
manner (EC50
Norepinephrine Induces Vascular Endothelial Growth Factor
Gene Expression in Brown Adipocytes through a
-Adrenoreceptor/cAMP/Protein Kinase A Pathway Involving Src but
Independently of Erk1/2*
,
90 nM). Also, the
hypoxia-mimicking agent cobalt, as well as serum and phorbol ester,
induced VEGF expression, but the effect of NE was additive to each of
these factors, implying that a separate signaling mechanism for the
NE-mediated induction was activated. The NE effect was abolished by
propranolol and mimicked by isoprenaline or BRL-37344 and was thus
mediated via 
-adrenoreceptors. The NE-induced VEGF expression was
fully cAMP mediated, an effect which was inhibited by H-89 and thus was
dependent on protein kinase A activity. Involvement of other adrenergic
signaling pathways (
1-adrenoreceptors, Ca2+,
protein kinase C, 2-adrenoreceptors, and pertussis
toxin-sensitive Gi-proteins) was excluded. The specific
inhibitor of Src tyrosine kinases, PP2, markedly reduced the
stimulation by NE, which demonstrates that a cAMP-dependent
Src-mediated pathway is positively connected to VEGF expression.
However, inhibition of Erk1/2 MAP kinases by PD98059 was without
effect. NE did not prolong VEGF mRNA half-life and its effect was
thus transcriptional, and was independent of protein synthesis. These
results demonstrate that adrenergic stimulation, through
-adrenoreceptor/cAMP/protein kinase A signaling, recruits a pathway
that branches off from the NE-activated Src-Erk1/2 cascade to enhance
transcription of the VEGF gene.
*
This work was supported by a grant from the Swedish Cancer
Foundation and by the Swedish Natural Science Research Council.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.: 46-8-164130;
Fax: 46-8-156756; E-mail: mf@zoofys.su.se.
§
On leave from the Institute of Cell Biophysics, Russian Academy of
Sciences, 142 292 Pushchino, Russia.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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