Placenta growth factor expression is regulated by hydrogen peroxide in vascular smooth muscle cells

Abstract

When supply arteries become occluded, blood is diverted through preexisting collateral vessels. Shear stress arising from this increase in blood flow provides the initial physiological stimulus for expansion of the collateral circulation, a process termed arteriogenesis. Endothelial cells (EC) respond to increased shear stress by releasing a variety of mediators that can act on underlying smooth muscle cells (SMC). Placenta growth factor (PLGF) is known to mediate certain aspects of arteriogenesis, such as recruitment of monocytes to the vessel wall. Therefore, we tested whether SMC PLGF expression is influenced by mediators released by EC. We used A10 SMC cultured with medium that had been conditioned by EOMA EC for 4 days as a model. We found that EC-conditioned medium is able to upregulate PLGF gene expression in A10 SMC. Further experiments identified hydrogen peroxide (H(2)O(2)) as a key mediator of this response. We confirmed the physiological relevance of this mechanism in primary human coronary artery SMCs by demonstrating that exogenous H(2)O(2) specifically upregulates PLGF gene and protein expression. We also demonstrated that the physiological stimulus of shear stress raises endogenous H(2)O(2) levels in media into the range found to increase PLGF expression. In this study, we demonstrate that EC-released H(2)O(2) acts as a positive regulator of PLGF gene and protein expression in vascular SMC. To our knowledge, this is the first study to describe H(2)O(2) as a regulator of PLGF expression and therefore an upstream mediator of PLGF-driven arteriogenesis.

Fluid shear stress upregulates placental growth factor in the vessel wall via NADPH oxidase 4

“…PLGF mRNA was increased in EC immediately after exposure to shear stress, whereas the increase in PLGF protein levels became detectable 8 h after exposure to shear stress. This time course is similar to the time course we previously reported for PLGF upregulation by H 2 O 2 in SMC (48). We also previously showed that PLGF protein levels can be regulated independently of PLGF mRNA levels (47).…”

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

“…We further hypothesized that regulation of PLGF expression in SMC would be endothelium-dependent, since the shear signal is sensed by endothelium as discussed above. In agreement with this hypothesis, we previously reported that physiological levels of hydrogen peroxide (H 2 O 2 ) are released from EC in response to shear stress, and that H 2 O 2 can act as a paracrine mediator to increase PLGF gene and protein expression in vascular SMC (13). H 2 O 2 has received increasing attention as an important physiological signaling molecule in vascular biology.…”

Exercise Training and Peripheral Arterial Disease

“…Since inhibition of SOD causes decreased H2O2 levels in addition to increased O2 − , another interpretation of these results is that H2O2 is the ROS species required for arteriogenesis. In agreement with this hypothesis, Shaw et al recently demonstrated that the arteriogenic mediator placenta growth factor (PLGF) is upregulated by H2O2 in vascular smooth muscle cells (838). The role of H2O2 in vascular physiology has been recently reviewed (32, 783).…”