Characteristics of Inflammatory and Normal Endothelial Exosomes on Endothelial Function and the Development of Hypertension.

Abstract

Endothelial dysfunction is associated with the development of hypertension. We hypothesize that inflammatory and normal endothelial exosomes play their roles by mediating endothelial function, and they induce endothelial angiogenesis through different signaling pathways. Endothelial cell-derived exosomes were isolated from the human umbilical vein endothelial cells (HUVECs) treated with (TExo) or without (CExo) tumor necrosis factor (TNF)-α. We monitored dermal microcirculation profiles in spontaneously hypertensive rats (SHRs) and WKY rats using a laser Doppler imager and a laser Doppler perfusion and temperature monitor. Tube formation, levels of angiogenesis-related proteins in HUVEC-conditioned media, and reactive oxygen species (ROS) levels were assessed following TNF-α, CExo, or TExo treatments. Western blot analysis was conducted to examine signaling proteins associated with inflammation and ROS. The results showed increased blood perfusion and the mean amplitude of endothelial oscillator in SHRs following CExo administration. TNF-α, CExo, and TExo treatments promoted endothelial tube formation and elevated levels of angiogenic factors and ROS. TExo significantly increased phosphorylation levels of STAT3, p38, and level of NF-κB, while decreasing phosphorylation levels of JNK and Erk (P < 0.01 or P < 0.05). CExo significantly increased STAT3 phosphorylation and reduced JNK and Erk phosphorylation (all P < 0.01). In conclusion, TNF-α and TExo induce inflammatory and pathological angiogenesis via the NF-κB pathway, while CExo exhibits a physiologically pro-angiogenic effect on endothelial cells. Increased ROS, interplaying with inflammatory signals, contribute to exosome-mediated alterations of endothelial function, thereby playing a role in the development of hypertension.