Role of Thioredoxin-interacting protein in VEGF's survival and angiogenic signal in endothelial cells

Project: Research

Investigators

  • Mohammed Anwar Abdelsaid (PI)

Description

Although physiological angiogenesis is important for recovery after stroke and myocardial infarction, pathological angiogenesis emphasizes a great clinical significance as in tumor growth and diabetic retinopathy. Vascular endothelial growth factor (VEGF) is one of the potent angiogenic growth factors that maintain endothelial cells survival and migration. The goal of this project is to examine the impact of the balance between the reactive oxygen species and cellular antioxidant defense in mediating VEGF's survival and angiogenic signals. Our group previously showed that VEGF stimulates the production of low levels of peroxynitrite to mediate its signal. In contrast, my recent study showed that high levels of peroxynitrite reduce antioxidant defense and impair VEGF's survival signal. Thioredoxin-interacting protein (Txnip) inhibits the activity of thioredoxin, a major cellular antioxidant and hence causes oxidative stress. My preliminary studies using Txnip deficient mice (TKO) showed significant increases in the thioredoxin reductase activity, reduced glutathione levels and reduction in peroxynitrite formation, however VEGF-mediated survival and revascularization were impaired in response to hypoxia. My preliminary studies using microvascular endothelial cells showed that VEGF can transiently alter the cellular redox state and that peroxynitrite increase focal adhesion kinase (FAK) phosphorylation and cause oxidative inhibition of low molecular weight protein tyrosine phosphatase (LMW-PTP), regulators of focal adhesion assembly. Cellular migration was significantly reduced in response to VEGF after silencing Txnip expression. Therefore, these finding lead me to hypothesize that the balance in redox state and Txnip expression are essential for VEGF's survival and angiogenic signal and in particular to regulate FAK phosphorylation and LMW-PTP activity.
Award amount$43,540.00
Award date07/01/2010
Program typePredoctoral Fellowship
Award ID10PRE3660004
Effective start/end date07/01/201012/16/2011
StatusFinished