title: Differential roles of prostaglandin E-type receptors in activation of hypoxia-inducible factor 1 by prostaglandin E1 in vascular-derived cells under non-hypoxic conditions.
abstract: Prostaglandin E1 (PGE1), known pharmaceutically as alprostadil, has vasodilatory properties and is used widely in various clinical settings. In addition to acute vasodilatory properties, PGE1 may exert beneficial effects by altering protein expression of vascular cells. PGE1 is reported to be a potent stimulator of angiogenesis via upregulation of VEGF expression, which is under the control of the transcription factor hypoxia-inducible factor 1 (HIF-1). However, the molecular mechanisms behind the phenomenon are largely unknown. In the present study, we investigated the mechanism by which PGE1 induces HIF-1 activation and VEGF gene expression in human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs), both vascular-derived cells. HUVECs and HASMCs were treated with PGE1 at clinically relevant concentrations under 20% O2 conditions and HIF-1 protein expression was investigated. Expression of HIF- 1α protein and the HIF-1-downstream genes were low under 20% O2 conditions and increased in response to PGE1 treatment in both HUVECs and HASMCs in a dose- and time-dependent manner under 20% O2 conditions as comparable to exposure to 1% O2 conditions. Studies using EP-receptor-specific agonists and antagonists revealed that EP1 and EP3 are critical to PGE1-induced HIF-1 activation. In vitro vascular permeability assays using HUVECs indicated that PGE1 increased vascular permeability in HUVECs. Thus, we demonstrate that PGE1 induces HIF- 1α protein expression and HIF-1 activation under non-hypoxic conditions and also provide evidence that the activity of multiple signal transduction pathways downstream of EP1 and EP3 receptors is required for HIF-1 activation.
authors.affiliation: Department of Anesthesia, Kyoto University Hospital , Kyoto , Japan ; Department of Anesthesiology, Tohoku University Hospital , Sendai , Japan.
authors.forename: Kengo
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Anesthesiology, Kansai Medical University , Hirakata, Osaka , Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Nishi
authors.affiliation: Department of Anesthesiology, Kansai Medical University , Hirakata, Osaka , Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takabuchi
authors.affiliation: Department of Anesthesia, Kyoto University Hospital , Kyoto , Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kai
authors.affiliation: Department of Anesthesia, Kyoto University Hospital , Kyoto , Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Matsuyama
authors.affiliation: Department of Anesthesiology, Tohoku University Hospital , Sendai , Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Kurosawa
authors.affiliation: Department of Anesthesia, Tazuke Kofukai Medical Research Institute Kitano Hospital , Osaka , Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Adachi
authors.affiliation: Minase Research Institutes, Research Headquarters, Ono Pharmaceutical , Osaka , Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Maruyama
authors.affiliation: Department of Anesthesia, Kyoto University Hospital , Kyoto , Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Anesthesiology, Kansai Medical University , Hirakata, Osaka , Japan.
authors.forename: Kiichi
authors.initials: K
authors.lastname: Hirota
keywords: Angiogenesis; EP receptor; Human endothelial cells; Human smooth muscle cells; Hypoxia-inducible factor; Prostaglandin E1; VEGF