Post-transcriptional regulation of placenta growth factor mRNA by hydrogen peroxide

In tissues containing pre-existing collateral vessels, occlusion of an upstream supply artery results in diversion of blood flow through these vessels, protecting the distal tissue from ischemia. The sudden rise in blood flow through collateral vessels exerts shear stress upon the vessel wall, thereby providing the initial stimulus for arteriogenesis. Arteriogenesis, the structural expansion of collateral circulation, involves smooth muscle cell (SMC) proliferation which leads to increased vessel diameter and wall thickness. Since shear is sensed at the level of endothelial cells (EC), communication from EC to the underlying SMC must occur as part of this process. We previously reported that endothelial cells (EC) exposed to shear stress release hydrogen peroxide (H2O2), and that H2O2 can signal vascular SMC to increase gene and protein expression of placenta growth factor (PLGF), a known mediator of arteriogenesis. The purpose of the current study was to further elucidate the mechanism whereby PLGF is regulated by H2O2. We found that a single, physiological dose of H2O2 increases PLGF mRNA half-life, but has no effect on PLGF promoter activity, in human coronary artery SMC (CASMC). We further demonstrated that the H2O2-induced increase in PLGF mRNA levels partially relies on p38 MAPK, JNK and ERK1/2 pathways. Finally, we showed that chronic exposure to pathological levels of H2O2 further increases PLGF mRNA levels, but does not result in a corresponding increase in PLGF secreted protein. These data suggest that PLGF regulation has an important translational component. To our knowledge, this is the first study to characterize post-transcriptional regulation of PLGF mRNA by H2O2 in vascular SMC. These findings provide new insights into the regulation of this important growth factor and increase our understanding of PLGF-driven arteriogenesis. (C) 2012 Elsevier Inc. All rights reserved.