Peroxynitrite increases VEGF expression in vascular endothelial cells via STAT3

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• Increased vascular endothelial growth factor (VEGF) expression is linked to oxidative stress and peroxynitrite formation in diseases like diabetic microangiopathy, tumor angiogenesis, and atherosclerosis.
• Peroxynitrite is implicated in various pathological conditions.

Purpose of the Study:

• To investigate whether peroxynitrite stimulates VEGF expression.
• To elucidate the molecular mechanisms underlying peroxynitrite-induced VEGF expression.

Main Methods:

• Microvascular endothelial cells were treated with exogenous peroxynitrite.
• VEGF mRNA and protein levels were quantified.
• Activation and nuclear translocation of transcription factors STAT3 and HIF-1 were assessed.
• Dominant-negative STAT3 and transcription inhibitors were used to probe mechanisms.

Main Results:

• Exogenous peroxynitrite induced a time- and dose-dependent increase in VEGF mRNA and protein in endothelial cells.
• Peroxynitrite activated STAT3, causing its nuclear translocation, but did not affect HIF-1.
• Inhibition of STAT3 or transcription blocked the peroxynitrite-induced increase in VEGF mRNA.
• Protein synthesis inhibition did not affect the increase in VEGF mRNA.

Conclusions:

• Peroxynitrite stimulates VEGF expression in vascular endothelial cells.
• STAT3 activation is a critical mediator of peroxynitrite-induced VEGF expression.
• This pathway highlights a molecular mechanism linking oxidative stress to VEGF production in disease.