title: Mice deficient in galectin-1 exhibit attenuated physiological responses to chronic hypoxia-induced pulmonary hypertension.
abstract: Pulmonary hypertension (PH) is characterized by sustained vasoconstriction, with subsequent extracellular matrix (ECM) production and smooth muscle cell (SMC) proliferation. Changes in the ECM can modulate vasoreactivity and SMC contraction. Galectin-1 (Gal-1) is a hypoxia-inducible beta-galactoside-binding lectin produced by vascular, interstitial, epithelial, and immune cells. Gal-1 regulates SMC differentiation, proliferation, and apoptosis via interactions with the ECM, as well as immune system function, and, therefore, likely plays a role in the pathogenesis of PH. We investigated the effects of Gal-1 during hypoxic PH by quantifying 1) Gal-1 expression in response to hypoxia in vitro and in vivo and 2) the effect of Gal-1 gene deletion on the magnitude of the PH response to chronic hypoxia in vivo. By constructing and screening a subtractive library, we found that acute hypoxia increases expression of Gal-1 mRNA in isolated pulmonary mesenchymal cells. In wild-type (WT) mice, Gal-1 immunoreactivity increased after 6 wk of hypoxia. Increased expression of Gal-1 protein was confirmed by quantitative Western analysis. Gal-1 knockout (Gal-1(-/-)) mice showed a decreased PH response, as measured by right ventricular pressure and the ratio of right ventricular to left ventricular + septum wet weight compared with their WT counterparts. However, the number and degree of muscularized vessels increased similarly in WT and Gal-1(-/-) mice. In response to chronic hypoxia, the decrease in factor 8-positive microvessel density was similar in both groups. Vasoreactivity of WT and Gal-1(-/-) mice was tested in vivo and with use of isolated perfused lungs exposed to acute hypoxia. Acute hypoxia caused a significant increase in RV pressure in wild-type and Gal-1(-/-) mice; however, the response of the Gal-1(-/-) mice was greater. These results suggest that Gal-1 influences the contractile response to hypoxia and subsequent remodeling during hypoxia-induced PH, which influences disease progression.
authors.affiliation: Cardiovascular Pulmonary Research Laboratory, Division of Cardiology and Department of Medicine, University of Colorado Health Science Center, 4200 E 9th Avenue, Denver, CO 80262, USA.
authors.forename: D
authors.initials: D
authors.lastname: Case
authors.forename: D
authors.initials: D
authors.lastname: Irwin
authors.forename: C
authors.initials: C
authors.lastname: Ivester
authors.forename: J
authors.initials: J
authors.lastname: Harral
authors.forename: K
authors.initials: K
authors.lastname: Morris
authors.forename: M
authors.initials: M
authors.lastname: Imamura
authors.forename: M
authors.initials: M
authors.lastname: Roedersheimer
authors.forename: A
authors.initials: A
authors.lastname: Patterson
authors.forename: M
authors.initials: M
authors.lastname: Carr
authors.forename: M
authors.initials: M
authors.lastname: Hagen
authors.forename: M
authors.initials: M
authors.lastname: Saavedra
authors.forename: J
authors.initials: J
authors.lastname: Crossno
authors.forename: K A
authors.initials: KA
authors.lastname: Young
authors.forename: E C
authors.initials: EC
authors.lastname: Dempsey
authors.forename: F
authors.initials: F
authors.lastname: Poirier
authors.forename: J
authors.initials: J
authors.lastname: West
authors.forename: S
authors.initials: S
authors.lastname: Majka
mesh_terms: D000818:Animals; D001483:Base Sequence; D002908:Chronic Disease; D017931:DNA Primers / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism; D037483:Galectin 1 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000503:physiopathology*; D000860:Hypoxia / Q000150:complications* / Q000503:physiopathology*; D066298:In Vitro Techniques; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000378:metabolism / Q000473:pathology; D012756:Sheep; D014655:Vascular Resistance / Q000502:physiology
chemical_list: D017931:DNA Primers; D037483:Galectin 1