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Vascular endothelial growth factor (VEGF) promotes endothelial survival and inhibits atherosclerosis progression. Endothelial apoptosis is potently inhibited by VEGF. Our initial observations showed that longer-term VEGF exposure increased resistance to apoptosis far exceeding the early effect. We hypothesized that VEGF upregulates poly(ADP- ribose)-polymerase-1 (PARP), a caspase target, and sought to determine the impact of PARP regulation on apoptosis in endothelial cells and human arteries.
Human endothelial cells (primary, macro-/microvascular lines) incubated with VEGF-A(165) 10-12-10-8M showed a time-dependent increase in apoptosis resistance: Short-term VEGF incubation reduced apoptosis by 65% (p<0.05) induced by the αv-integrin inhibitor cRGDfV. Repeated longer-term incubation reduced apoptosis by more than 90% (p<0.05). VEGF dose-dependently induced PARP protein and mRNA production leading to increased PARP activity in the presence or absence of cRGDfV. FGF-2 or TGFβ had no influence on PARP expression. In mRNA knockdown experiments, the anti-apoptotic effect of VEGF was aborted by PARP siRNA. VEGF signaling leading to increased PARP expression involved VEGF receptor-2, which was colocalized with neuropilin-1, and signal transduction molecules SAPK/JNK and Akt. Immunohistochemistry of human atherosclerotic compared to normal arteries demonstrated increased PARP expression in the endothelium and prominent vascular VEGF expression. In an arterial organ culture model, VEGF induced increased endothelial PARP expression.
VEGF exerts a major part of its anti-apoptotic effect on endothelial cells through the regulation of PARP gene expression. PARP counteracts or promotes apoptotic cell death depending on the cellular activation state. In human arteries, VEGF regulation of PARP protects endothelial integrity.
Key words: apoptosis, atherosclerosis, cardiovascular diseases, endothelium