title: The pathophysiological basis of chronic hypoxic pulmonary hypertension in the mouse: vasoconstrictor and structural mechanisms contribute equally.
abstract: Chronic hypoxic pulmonary hypertension is characterized by a sustained increase in pulmonary arterial pressure due to abnormally elevated pulmonary vascular resistance. This increased vascular resistance was previously thought to be due largely to changes in the structure of the pulmonary vasculature, i.e. lumen narrowing due to wall hypertrophy and loss of vessels. Recently, this model has been challenged by the demonstration that hypoxic pulmonary hypertension in the rat is caused almost completely by sustained vasoconstriction. The contribution of this vasocontriction to hypoxic pulmonary hypertension has not been examined directly in other species. We exposed groups of mice to hypoxia (10% O(2)) or normoxia for 3 weeks, following which the lungs were removed post mortem, and vascular resistance was measured in an isolated, ventilated, perfused preparation. Mean pulmonary vascular resistance was significantly increased in hypoxic compared with control normoxic lungs. The rho kinase inhibitor Y27635 (10(-4)m) (Tocris Bioscience, Bristol, United Kingdom.) significantly reduced the mean (± SEM) hypoxia induced increase by 45.4 (10.8)%, implying that structural vascular changes acounted for the remainder of the hypoxic increase. Stereological quantification showed a significant reduction in the mean lumen diameter of the fully relaxed vessels in hypoxic lungs compared with normoxic control lungs; there was no intra-acinar vessel loss. Thus, in contrast to the rat, hypoxic pulmonary hypertension in the mouse is due to two mechanisms contributing equally: sustained vasoconstriction and structural lumen narrowing of intra-acinar vessels. These important species diferences must be considered when using genetically mutated mice to investigate the mechanisms underlying pulmonary hypertension.
authors.affiliation: University College Dublin, School of Medicine and Medical Sciences, Conway Institute, Dublin, Ireland.
authors.forename: Edwina
authors.initials: E
authors.lastname: Cahill
authors.forename: Simon C
authors.initials: SC
authors.lastname: Rowan
authors.forename: Michelle
authors.initials: M
authors.lastname: Sands
authors.forename: Mark
authors.initials: M
authors.lastname: Banahan
authors.forename: Donal
authors.initials: D
authors.lastname: Ryan
authors.forename: Katherine
authors.initials: K
authors.lastname: Howell
authors.forename: Paul
authors.initials: P
authors.lastname: McLoughlin
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology*; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000187:drug effects / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D014662:Vasoconstrictor Agents; D054460:rho-Associated Kinases