Regulation of vascular endothelial growth factor in cardiac myocytes.
Collateral blood vessels supplement normal coronary blood flow and coronary blood flow compromised by coronary artery disease, thereby protecting the myocardium from ischemia. Collateral vessel formation is the result of angiogenesis. Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a secreted mitogen specific for endothelial cells and an extremely potent angiogenic factor. In the present study, VPF/VEGF mRNA and protein were demonstrated to be markedly stimulated in primary rat cardiac myocytes in vitro in response to reduction of the oxygen tension to 1% or inhibition of the electron transport chain. Four isoforms of VPF/VEGF were coordinately regulated by hypoxia, including a novel isoform not previously described. Phorbol ester and the depolarizing agent veratridine, stimulators of protein kinase C and calcium influx, respectively, were found to markedly increase VPF/VEGF mRNA expression in cardiac myocytes. Forskolin, a potent stimulator of adenylate cyclase, produced a small but significant increase in VPF/VEGF mRNA expression in the cardiac myocytes. However, only H7, an inhibitor of protein kinase C, inhibited the hypoxic induction of VPF/VEGF mRNA; inhibitors of calcium influx and the calcium-calmodulin-dependent protein kinase II as well as inhibition of protein kinase A did not block the hypoxic induction of VPF/VEGF mRNA. This suggests that more than one signal transduction pathway is involved in regulating VPF/VEGF expression. The sensor that regulates the expression of hypoxia-responsive genes has been proposed to be a heme protein. Consistent with this model, transition metals initiate a genetic program similar to hypoxia.(ABSTRACT TRUNCATED AT 250 WORDS)
Levy
A P
AP
Cardiology Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Levy
N S
NS
Loscalzo
J
J
Calderone
A
A
Takahashi
N
N
Yeo
K T
KT
Koren
G
G
Colucci
W S
WS
Goldberg
M A
MA
D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000737:chemistry; D004730:Endothelium, Vascular / Q000187:drug effects; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis* / Q000737:chemistry; D009206:Myocardium / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D015290:Second Messenger Systems; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D008222:Lymphokines; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D003035:Cobalt