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Regulation of vascular endothelial growth factor in cardiac myocytes
A P Levy1, N S Levy, J Loscalzo
1Cardiology Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
Insights
Collateral blood vessel growth, driven by vascular endothelial growth factor (VEGF), protects the heart during low oxygen. Protein kinase C signaling is key to this process in cardiac cells.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Angiogenesis Research
Background:
- Collateral blood vessels are crucial for maintaining myocardial perfusion, especially in coronary artery disease.
- Angiogenesis, the formation of new blood vessels, is vital for collateral circulation.
- Vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), is a potent stimulator of angiogenesis.
Purpose of the Study:
- To investigate the regulation of VPF/VEGF expression in cardiac myocytes under hypoxic conditions.
- To identify the signaling pathways involved in hypoxia-induced VPF/VEGF expression.
- To explore the role of different signaling molecules in VPF/VEGF regulation.
Main Methods:
- Primary rat cardiac myocytes were cultured in vitro.
- Hypoxia was induced by reducing oxygen tension to 1% or inhibiting the electron transport chain.
- VPF/VEGF mRNA and protein levels were measured.
- The effects of various signaling pathway modulators (phorbol ester, veratridine, forskolin, H7) were assessed.
Main Results:
- Hypoxia markedly stimulated VPF/VEGF mRNA and protein expression in cardiac myocytes.
- Four VPF/VEGF isoforms, including a novel one, were coordinately regulated by hypoxia.
- Phorbol ester and veratridine increased VPF/VEGF mRNA expression.
- Only protein kinase C inhibition by H7 blocked hypoxic induction of VPF/VEGF mRNA.
- Other signaling inhibitors did not block hypoxic induction, suggesting multiple pathways.
Conclusions:
- Hypoxia significantly upregulates VPF/VEGF expression in cardiac myocytes through multiple signaling pathways.
- Protein kinase C plays a critical role in the hypoxic induction of VPF/VEGF.
- These findings contribute to understanding the molecular mechanisms of therapeutic angiogenesis in cardiovascular disease.
Abstract:
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)