title: Soluble receptor for advanced glycation end products (sRAGE) attenuates haemodynamic changes to chronic hypoxia in the mouse.
abstract: The calgranulin-like protein MTS1/S100A4 and the receptor for advanced glycation end-products (RAGE) have recently been implicated in mediating pulmonary arterial smooth muscle cell proliferation and vascular remodelling in experimental pulmonary arterial hypertension (PH). Here, the effects of RAGE antagonism upon 2 weeks of hypobaric hypoxia (10% O2)-induced PH in mice were assessed. Treatment with sRAGE was protective against hypobaric hypoxia-induced increases in right ventricular pressure but distal pulmonary vascular remodelling was unaffected. Intralobar pulmonary arteries from hypobaric hypoxic mice treated with sRAGE showed protection against a hypoxia-induced reduction in compliance. However, a combination of sRAGE and hypoxia also dramatically increased the force of contractions to KCl and 5-HT observed in these vessels. The acute addition of sRAGE to the organ bath produced a small, sustained contraction in intralobar pulmonary vessels and produced a synergistic enhancement of the maximal force of contraction in subsequent concentration-response curves to 5-HT. sRAGE had no effect on 5-HT-induced proliferation of Chinese hamster lung fibroblasts (CCL39), used since they have a similar pharmacological profile to mouse pulmonary fibroblasts but, surprisingly, produced a marked increase in hypoxia-induced proliferation. These data implicate RAGE as a modulator of both vasoreactivity and of proliferative processes in the response of the pulmonary circulation to chronic-hypoxia.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom. Electronic address: david.farmer@florey.edu.au.
authors.forename: David G S
authors.initials: DG
authors.lastname: Farmer
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom. Electronic address: marie-ann.ewart@glasgow.ac.uk.
authors.forename: Marie-Ann
authors.initials: MA
authors.lastname: Ewart
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom. Electronic address: kirsty.mair@glasgow.ac.uk.
authors.forename: Kirsty M
authors.initials: KM
authors.lastname: Mair
authors.affiliation: Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary & Life Sciences, University of Glasgow, G12 8QQ Glasgow, United Kingdom. Electronic address: simon.kennedy@glasgow.ac.uk.
authors.forename: Simon
authors.initials: S
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000502:physiology; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism*; D006439:Hemodynamics; D006976:Hypertension, Pulmonary / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000502:physiology; D011651:Pulmonary Artery / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products / Q000008:administration & dosage / Q000378:metabolism*; D012701:Serotonin / Q000008:administration & dosage / Q000378:metabolism; D066253:Vascular Remodeling / Q000502:physiology
chemical_list: D000067759:Receptor for Advanced Glycation End Products; D012701:Serotonin
keywords: Fibroblasts; Hypoxia; MTS1/S100A4; Pulmonary hypertension; RAGE