title: Nitric oxide donors augment interleukin-1β-induced vascular endothelial growth factor in airway smooth muscle cells.
abstract: Angiogenesis and microvascular leakage are features of chronic inflammatory diseases of which molecular mechanisms are poorly understood. We investigated the effects of interleukin-1β (IL-1β) on the expression and secretion of vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) in porcine airway smooth muscle cells (PASMC) in relation to a nitric oxide (NO) pathway. Serum-deprived (48 h) PASMC were stimulated with IL-1β alone or with NO donor, L-arginine and/or NO synthase inhibitor L-NAME for 4 and 24 h. IL-1β did not affect PlGF release, but augmented VEGF release (2.4-fold) after 24 h. VEGF release was inhibited by L-NAME (531.8 ± 52 pg/ml), but restored and further elevated by L-arginine (1,529 ± 287 pg/ml). IL-1β up-regulated VEGF mRNA (1.8-fold) and this response was attenuated by L-NAME (1.1-fold) and augmented by L-arginine (3.8-fold) at 4 h. Restoration of a NO pathway by L-arginine in L-NAME-treated cells resulted in elevated VEGF mRNA levels (2.2-fold). [(3)H]Thymidine incorporation assay revealed enhanced porcine pulmonary artery endothelial cell proliferation in response to IL-1β, VEGF and PlGF, and this mitogenic effect was not influenced via the NO pathway. Our results suggest that a NO pathway modulates VEGF synthesis during inflammation contributing to bronchial angiogenesis and vascular leakage.
authors.affiliation: Department of Pathology, VUmc University Medical Center, De Boelelaan 1117, 1081 HV, Amsterdam, The Netherlands, h.sharma@vumc.nl.
authors.forename: Hari S
authors.initials: HS
authors.lastname: Sharma
authors.forename: Vijay K T
authors.initials: VK
authors.lastname: Alagappan
authors.forename: Anna
authors.initials: A
authors.lastname: Willems-Widyastuti
authors.forename: Wolter J
authors.initials: WJ
authors.lastname: Mooi
authors.forename: Willem I
authors.initials: WI
authors.lastname: de Boer
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D053583:Interleukin-1beta / Q000494:pharmacology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000378:metabolism; D011651:Pulmonary Artery / Q000166:cytology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D053583:Interleukin-1beta; D020030:Nitric Oxide Donors; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester