Mice deficient in galectin-1 exhibit attenuated physiological responses to chronic hypoxia-induced pulmonary hypertension

• Published in: American journal of physiology. Lung cellular and molecular physiology Vol. 292; no. 1; pp. L154 - L164
• Main Authors: Case, D, Irwin, D, Ivester, C, Harral, J, Morris, K, Imamura, M, Roedersheimer, M, Patterson, A, Carr, M, Hagen, M, Saavedra, M, Crossno, J., Jr, Young, K. A, Dempsey, E. C, Poirier, F, West, J, Majka, S
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.01.2007
• Subjects: Animals; Anoxia; Base Sequence; Chronic Disease; DNA Primers; DNA Primers - genetics; Extracellular Matrix; Extracellular Matrix - metabolism; Galectin 1; Galectin 1 - deficiency; Galectin 1 - genetics; Galectin 1 - physiology; Gene expression; Glycoproteins; Human health and pathology; Hypertension, Pulmonary; Hypertension, Pulmonary - etiology; Hypertension, Pulmonary - physiopathology; Hypoxia; Hypoxia - complications; Hypoxia - physiopathology; In Vitro Techniques; Life Sciences; Lung; Lung - blood supply; Lung - metabolism; Lung - pathology; Lungs; Mesenchymal Stem Cells; Mesenchymal Stromal Cells - metabolism; Mesenchymal Stromal Cells - pathology; Mice; Mice, Knockout; Microcirculation; Microcirculation - metabolism; Microcirculation - pathology; Muscle, Smooth, Vascular; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Pulmonology and respiratory tract; Respiratory diseases; Rodents; Sheep; Vascular Resistance; Vascular Resistance - physiology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00192.2006

1 Cardiovascular Pulmonary Research Laboratory, 2 Division of Pulmonary Sciences and Critical Care Medicine, 3 Division of Cardiology and Department of Medicine, University of Colorado Denver Health Science Center, and 4 Denver Veterans Administration Medical Center, Denver, Colorado; and 5 Department of Developmental Biology, Institut Jacques Monod, Centre National de la Recherche Scientifique Unité Mixté de Recherche 7592, Universités Paris 6 and 7, Paris, France Submitted 1 June 2006 ; accepted in final form 17 August 2006 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 -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. vascular remodeling; right ventricular failure; immune response; extracellular matrix Address for reprint requests and other correspondence: S. Majka, Univ. of Colorado Health Science Center, SON 3928, Mail Stop B-133, 4200 E 9th Ave., Denver, CO 80262 (e-mail: Susan.majka{at}uchsc.edu )