Abstract 16089: Fluoxetine Rescues Psychological Stress-Induced Impairment of Neovascularisation
Background: Psychological stress (PS) and clinical depression are associated with a significant increase in cardiovascular mortality and morbidity. Here we tested the hypothesis that the antidepressant fluoxetine (FX) might improve ischemia-induced neovascularisation in animals exposed to PS.
Methods and results: Balb/c mice were subjected to restraint stress in a well ventilated tube for 20 minutes each day, 5 days per week. Non-stressed control mice were left unperturbed in their cage with free access to food and water. Stressed mice were treated or not with FX (160 mg/L in drinking water), starting 3 weeks before the induction of PS. After two weeks of PS, hindlimb ischemia was surgically provoked by femoral artery removal and blood flow perfusion was evaluated by Laser Doppler imaging. Stressed mice showed a significant decrease in blood flow recuperation 14 days (Doppler flow ratio : 0.61±0.02 vs 0.78±0.05; p<0.05) and 21 days (0.66±0.02 vs 0.80±0.07; p<0.05) post-ischemia. This was associated with a significant reduction of capillary density in ischemic muscles (180±5 vs 350±14 capillaries/mm2, p<0.001). However, we found that stressed mice treated with FX exhibited a complete rescue of blood flow recuperation (Doppler flow ratio : 0.81±0.03; p<0.01) and capillary density in ischemic muscles (359±9 capillaries/mm2; p<0.001). We also demonstrate that PS is associated with a decreased activation of angiogenic signals in ischemic muscles (VEGF, Akt, p44/42 MAPK) that can be rescued by FX treatment. Endothelial progenitor cells (EPCs) have an important role in postnatal neovascularisation. We found that PS is associated with reduced number of EPCs, increased oxidative stress levels, and impairment of EPC angiogenic activities (adhesion, migration, integration into tubules). Importantly, FX can rescue EPC number, oxidative stress levels and EPC functional activities in mice exposed to PS.
Conclusions: PS is associated with reduced neovascularisation following ischemia, which can be rescued by FX treatment. Potential mechanisms include decreased oxidative stress levels, improved activation of angiogenic pathways, and rescue of EPC number / functional activities.
- © 2010 by American Heart Association, Inc.