Norepinephrine upregulates vascular endothelial growth factor in rat cardiac myocytes by a paracrine mechanism.
Norepinephrine has growth-promoting effects in cardiac myocytes. The present study in cultured neonatal rat cardiac myocytes tested the hypothesis that norepinephrine also stimulates expression of vascular endothelial growth factor (VEGF), an important angiogenic factor. As assessed by polymerase chain reaction cardiac myocytes and non-myocytes expressed all three isoforms of rat VEGF, with the short isoform (VEGF 121 ) preferentially expressed in non-myocytes. When cardiac myocytes were stimulated with 1 micro M norepinephrine for 24 h in the presence or absence of the specific alpha - and beta -adrenoceptor antagonists prazosin and propranolol, respectively, VEGF mRNA levels and splice variant pattern did not change, whereas atrial natriuretic peptide mRNA levels increased 3 to 4-fold. CoCl(2) increased VEGF mRNA levels in cardiac myocytes five-fold. When cardiac myocytes were cultured with conditioned medium from non-myocytes that had been stimulated with norepinephrine for 24 h VEGF mRNA increased 2-fold. The increase was blocked by antibodies neutralizing TGF beta. These data suggest that norepinephrine stimulates myocardial angiogenesis by a paracrine mechanism that involves cardiac non-myocytes and TGF beta.
Weil
Joachim
J
Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, Germany. joachim.weil@klinik.uni-regensburg.de
Benndorf
Ralf
R
Fredersdorf
Sabine
S
Griese
Daniel P
DP
Eschenhagen
Thomas
T
D000262:Adenylyl Cyclases / Q000032:analysis; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D017398:Alternative Splicing; D000818:Animals; D000831:Animals, Newborn; D009320:Atrial Natriuretic Factor / Q000494:pharmacology; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D017077:Culture Media, Conditioned; D005786:Gene Expression Regulation / Q000187:drug effects; D014644:Genetic Variation; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology*; D019899:Paracrine Communication / Q000187:drug effects*; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*
D000317:Adrenergic alpha-Antagonists; D000319:Adrenergic beta-Antagonists; D017077:Culture Media, Conditioned; D020033:Protein Isoforms; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D003035:Cobalt; D009320:Atrial Natriuretic Factor; D011433:Propranolol; D000262:Adenylyl Cyclases; C018021:cobaltous chloride; D009638:Norepinephrine; D011224:Prazosin