Abstract
Chronic psychological stress (CPS) is a significant risk factor for thrombotic cardio-cerebrovascular diseases (TCVDs). Clinical data suggest that the α2-adrenergic receptor (AdR-α2) agonist dexmedetomidine (Dex) can influence coagulation in stress-exposed intensive care unit patients. Given the important role of protease-activated receptor-2 (PAR-2) in vascular pathobiology, we aimed to investigate the potential effects of Dex on stress-related thrombus formation, focusing on the PAR-2 signaling pathway. Eight-week-old male mice underwent non-stress and immobilization stress with Dex treatment for 2 weeks and were then subjected to carotid artery thrombosis induction using ferric chloride (FeCl3). On Day 14 post-stress, the mice exhibited increased thrombus weight and length, along with harmful alterations in the plasma levels of von Willebrand factor and metalloproteinase with thrombospondin Type 13 motifs. Additionally, arterial protein and/or mRNA levels of PAR-2, p-Akt, Bcl-2, cleaved caspase-3, cytochrome c, gp91phox, TNF-α, MCP-1, ICAM-1, VCAM-1, and TLR-4 were altered, accompanied by arterial endothelial loss. Dex treatment reversed these changes. Conversely, AdR-α2 blockage with yohimbine diminished the benefits of Dex. In vitro, Dex reduced stress serum-induced reactive oxygen species production and endothelial apoptosis, along with beneficial alterations in PAR-2, Bcl-2, and cytochrome c protein levels. Yohimbine diminished these effects. Thus, α2-adrenergic receptor activation appeared to mitigate stress-related thrombus formation in mice undergoing FeCl3-induced surgery, possibly by negatively regulating PAR-2 signaling. These findings suggest a potential therapeutic strategy for CPS-related thrombotic events in patients with TCVDs.