title: Psychological stress impairs ischemia-induced neovascularization: Protective effect of fluoxetine.
abstract: BACKGROUND
  Psychological stress (PS) has been associated with the development of cardiovascular diseases and adverse long-term outcomes after ischemic events. However, the precise mechanisms involved are not completely understood. Here we investigated the effect of PS on ischemia-induced neovascularization, and the potential therapeutic effect of fluoxetine in this condition.
  
  
  RESULTS
  Balb/c mice were subjected or not to chronic restraint stress. After 3 weeks, hindlimb ischemia was surgically induced by femoral artery removal. We found that blood flow recovery was significantly impaired in mice exposed to PS compared to controls (Doppler flow ratio (DFR) 0.61 ± 0.07 vs. 0.80 ± 0.07, p < 0.05). At the microvascular level, capillary density was significantly reduced in ischemic muscles of mice exposed to PS (38 ± 1 vs. 74 ± 3 capillaries per field, p < 0.001). This correlated with increased oxidative stress levels and reduced expression of VEGF and VEGF signalling molecules (p44/p42 MAPK, Akt) in ischemic muscles. We found that the number of pro-angiogenic cells (PACs) was significantly reduced in mice exposed to PS. In addition, oxidative stress levels (DCF-DA, DHE) were increased in PACs isolated from mice exposed to PS, and this was associated with impaired PAC functional activities (migration, adhesion, and integration into tubules). Importantly, treatment of mice exposed to PS with the selective serotonin reuptake inhibitor (SSRI) fluoxetine improved all the angiogenic parameters, and completely rescued PS-induced impairment of neovascularization.
  
  
  CONCLUSIONS
  PS impairs ischemia-induced neovascularization. Potential mechanisms involved include reduced activation of the VEGF pathway in ischemic tissues, increased oxidative stress levels and reduced number and functional activities of PACs. Our results suggest that fluoxetine may represent a novel therapeutic strategy to improve neovascularization and reduce ischemia in patients suffering from cardiovascular diseases and exposed to PS.
authors.affiliation: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Fritz
authors.initials: F
authors.lastname: Maingrette
authors.affiliation: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dussault
authors.affiliation: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Wahiba
authors.initials: W
authors.lastname: Dhahri
authors.affiliation: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Desjarlais
authors.affiliation: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Raphael
authors.initials: R
authors.lastname: Mathieu
authors.affiliation: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Julie
authors.initials: J
authors.lastname: Turgeon
authors.affiliation: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Paola
authors.initials: P
authors.lastname: Haddad
authors.affiliation: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Jessika
authors.initials: J
authors.lastname: Groleau
authors.affiliation: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada.
authors.forename: Gemma
authors.initials: G
authors.lastname: Perez
authors.affiliation: Department of Cardiovascular Research, Centre Hospitalier de l'Université de Montréal, Montréal, Québec, Canada. Electronic address: alain.rivard@umontreal.ca.
authors.forename: Alain
authors.initials: A
authors.lastname: Rivard
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D001783:Blood Flow Velocity / Q000187:drug effects; D001835:Body Weight; D002465:Cell Movement; D003094:Collagen / Q000737:chemistry; D004338:Drug Combinations; D042783:Endothelial Cells / Q000378:metabolism; D005473:Fluoxetine / Q000627:therapeutic use*; D006614:Hindlimb / Q000098:blood supply; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007511:Ischemia / Q000378:metabolism* / Q000523:psychology; D007797:Laminin / Q000737:chemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D018384:Oxidative Stress; D011509:Proteoglycans / Q000737:chemistry; D013315:Stress, Psychological; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D018687:Antidepressive Agents, Second-Generation; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; D042461:Vascular Endothelial Growth Factor A; D005473:Fluoxetine; C059485:matrigel; D003094:Collagen
keywords: Angiogenesis; Fluoxetine; Neovascularization; Psychological stress