title: Comparison of angiogenic and proliferative effects of three commonly used agents for pulmonary artery hypertension (sildenafil, iloprost, bosentan): is angiogenesis always beneficial?
abstract: OBJECTIVE
  Pulmonary artery hypertension (PAH) is devastating disease that has very serious outcomes. Dysregulated angiogenesis is one of the main responsible courses in pathophysiology of disease. Our experimental research intends to find out and compare the angiogenic effects of medications used sildenafil, iloprost, and bosentan in the treatment of PAH.
  
  
  METHODS
  This study was performed in Department of Biochemistry and Cancer and Stem Cell Research Laboratory of our institutes between August and October 2014. Angiogenic activity of sildenafil, iloprost, and bosentan were examined in vivo in chick chorioallantoic membrane (CAM) model and in vitro tube formation assay of human umbilical vein endothelial cells (HUVECs). Proliferative activity of these three agents was also determined through 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay on HUVECs.
  
  
  RESULTS
  In CAM assay, when compared to the control and drug groups, treatment with sildenafil solutions resulted in a significant dose-dependent increase (budding, sprouting, extravasation) on CAM vessel growth. While there was no significant proliferative effect with iloprost and bosentan, presence of sildenafil caused a statistically significant proliferation on HUVECs following 24 and 48 h incubation (p < 0.05) compared to the control group. Comparing the tube length/area ratio values, there was statistically significant increase in sildenafil group with respect to the other 2 groups (p < 0.05). Iloprost and bosentan did not show a significant effect.
  
  
  CONCLUSIONS
  The results provide evidence that sildenafil but not iloprost and bosentan induces angiogenesis in vitro and in vivo. Dysregulated angiogenesis, as an important pathophysiological part in the progression of PAH, may be triggered by the chronic ingestion of sildenafil in the long treatment period and may cause negative effects.
authors.affiliation: Department of Cardiovascular Surgery, Department of Anesthesiology, Department of Biochemistry; Gulhane Military Academy of Medicine, Ankara, Turkey. suat_doganci@yahoo.com.
authors.forename: S
authors.initials: S
authors.lastname: Doganci
authors.forename: V
authors.initials: V
authors.lastname: Yildirim
authors.forename: F
authors.initials: F
authors.lastname: Yesildal
authors.forename: G
authors.initials: G
authors.lastname: Erol
authors.forename: M
authors.initials: M
authors.lastname: Kadan
authors.forename: G
authors.initials: G
authors.lastname: Ozkan
authors.forename: F
authors.initials: F
authors.lastname: Avcu
authors.forename: T
authors.initials: T
authors.lastname: Ozgurtas
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D000077300:Bosentan; D049109:Cell Proliferation / Q000187:drug effects*; D002642:Chick Embryo; D004305:Dose-Response Relationship, Drug; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000188:drug therapy / Q000503:physiopathology; D016285:Iloprost / Q000494:pharmacology*; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: D043925:Angiogenesis Inducing Agents; D013449:Sulfonamides; D000068677:Sildenafil Citrate; D016285:Iloprost; D000077300:Bosentan