The Phosphodiesterase-5 Inhibitor Vardenafil Improves the Activation of BMP Signaling in Response to Hydrogen...

The pleiotropic roles of phosphodiesterase-5 inhibitors (PDE5is) in cardiovascular diseases have attracted attention. The effect of vardenafil (a PDE5i) is partly mediated through reduced oxidative stress, but it is unclear whether vardenafil protects against hydrogen peroxide (H₂O₂)-induced endothelial cell injury, and the molecular mechanisms that are involved remain unknown. We determined the protective role of vardenafil on H₂O₂-induced endothelial cell injury in cultured human umbilical vein endothelial cells (HUVECs).

Vardenafil decreased the number of TUNEL-positive cells, increased the Bcl2/Bax ratio, and ameliorated the numbers of BrdU-positive cells in H₂O₂-treated HUVECs. The bone morphogenetic protein receptor (BMPR)/p-Smad/MSX2 pathway was enhanced in response to H₂O₂, and vardenafil treatment could normalize this pathway. To determine whether the BMP pathway is involved, we blocked the BMP pathway using dorsomorphin, which abolished the protective effects of vardenafil. We found that vardenafil improved the H₂O₂-induced downregulation of BMP-binding endothelial regulator protein (BMPER), which possibly intersects with the BMP pathway in the regulation of endothelial cell injury in response to oxidative stress.

We demonstrated for the first time that exogenous H₂O₂ activates BMPR expression and promotes Smad1/5/8 phosphorylation. Additionally, vardenafil can attenuate H₂O₂-induced endothelial cell injury in HUVECs. Vardenafil decreases apoptosis through an improved Bcl-2/Bax ratio and increases cell proliferation. Vardenafil protects against endothelial cell injury through ameliorating the intracellular oxidative stress level and BMPER expression. The protective role of vardenafil on H₂O₂-induced endothelial cell injury is mediated through BMPR/p-Smad/MSX2 in HUVECs.