title: Vascular endothelial growth factor-induced nitric oxide- and PGI2-dependent relaxation in human internal mammary arteries: a comparative study with KDR and Flt-1 selective mutants.
abstract: The role of the vascular endothelial growth factors (VEGF) receptors (KDR and Flt-1) and their characteristics in VEGF-induced vasodilation in human vessels is unclear. This study investigated the in vitro vasorelaxant effects of KDR-selective (KDR-SM) and Flt-1-selective mutants (Flt-1-SM) in the human internal mammary artery (IMA). IMA segments (n = 183) taken from 48 patients were studied in organ baths. The cumulative concentration (-12 to -8 log10M)-relaxation curves were established for VEGF, KDR-SM, Flt-1-SM, and placenta growth factor (PlGF) in the absence or presence of indomethacin (INDO, 7 microM), N-nitro-L-arginine (L-NNA, 300 microM), L-NNA + oxyhemoglobin (HbO, 20 microM), or INDO + L-NNA + HbO. The VEGF-induced relaxation was abolished in endothelium-denuded IMA. In the endothelium-intact vessel rings, VEGF (63.2 +/- 3.9%) induced significantly more (P < 0.001) relaxation than Flt-1-SM (28.5 +/- 4.3%, 95% CI 18.1-51.3%), and PlGF (26.0 +/- 4.7%, 95% CI 17.6-56.8%). The maximal relaxation induced by KDR-SM (53.0 +/- 4.0%) was only slightly less than that by VEGF (P = 0.075) but significantly more than that by Flt-1-SM (P = 0.001, 95% CI 7.8-41.1%). Pretreatment of INDO or L-NNA + HbO significantly (P < 0.001) inhibited the relaxation by VEGF (21.2 +/- 3.9% or 23.3 +/- 4.3%) and KDR-SM (9.8 +/- 8.2% or 10.1 +/- 17.8%). INDO + L-NNA + HbO completely inhibited the relaxation by VEGF, KDR-SM, or Flt-1-SM. KDR may be the dominant receptor in mediating the VEGF-mediated relaxation, which is regulated by both PGI2 and nitric oxide but probably not by endothelium-derived hyperpolarizing factor, in the human IMA. This study gives insight into the characteristics of the VEGF-mediated vasodilation and provides a scientific basis for potential clinical application of VEGF/KDR-SM in ischemic heart disease.
authors.affiliation: Starr Academic Center, Providence Heart Institute, Department of Surgery, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Hongkui
authors.initials: H
authors.lastname: Jin
authors.forename: Zhi-Wu
authors.initials: ZW
authors.lastname: Chen
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Zioncheck
authors.forename: Anthony P C
authors.initials: AP
authors.lastname: Yim
authors.forename: Guo-Wei
authors.initials: GW
authors.lastname: He
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism* / Q000494:pharmacology; D005260:Female; D006801:Humans; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D008323:Mammary Arteries / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism* / Q000494:pharmacology; D019335:Nitroarginine / Q000494:pharmacology; D010108:Oxyhemoglobins / Q000494:pharmacology; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000494:pharmacology; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000145:classification / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
chemical_list: D010108:Oxyhemoglobins; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D042442:Vascular Endothelial Growth Factors; D000072483:Placenta Growth Factor; D019335:Nitroarginine; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D011464:Epoprostenol; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; D007213:Indomethacin