Submitted on June 1, 2006
Accepted on August 17, 2006
Mice Deficient in Galectin-1 Exhibit Attenuated Physiological Responses to Chronic Hypoxia Induced Pulmonary Hypertension
David Case1, David Irwin1, Charles Ivestor1, Julie Harral1, Kenneth Morris, Masatoshi Imamura1, Mark Roedersheimer1, Abby Patterson1, michelle carr1, Moira Hagen, Milene Saavedra1, Joseph Crossno Jr1, Katharine A Young1, Edward C. Dempsey2, Francoise Poirier3, James West1, and Susan M Majka1*
1 Medicine, University of Colorado HSC, Denver, Colorado, United States
2 Medicine, University of Colorado, Denver, Colorado, United States; CVP Lab/B-133, University of Colorado, Denver, Colorado, 80262, United States
3 Departement de Biologie du Developpement, Institut Jacques Monod, PARIS, Cedex 05, France
* To whom correspondence should be addressed. E-mail: susan.majka{at}uchsc.edu.
Pulmonary hypertension (PH) is characterized by sustained vasoconstriction with subsequent extracellular matrix (ECM) production and smooth muscle cell (SMC) proliferation. Changes in ECM can modulate vasoreactivity and SMC contraction. Galectin-1 (Gal-1) is a hypoxia-inducible B-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 pulmonary hypertensive response to chronic hypoxia in vivo. By constructing and screening a subtractive library, we found increased expression of Gal-1 mRNA in isolated pulmonary mesenchymal cells induced by acute hypoxic exposure. In wt mice, Gal-1 immunoreactivity increased following a 6-week exposure to hypoxia. Increased expression of Gal-1 protein was confirmed by quantitative Western analysis. Gal-1 knockout (Gal-1-/-) mice showed a decreased pulmonary hypertensive response, as measured by right ventricular pressures (RVP) and right ventricle over left ventricle plus septum (RV/LV+S) ratios compared to wt counterparts. However, the number and degree of muscularized vessels increased similarly in wt and Gal-1-/-. In response to chronic hypoxia, both groups of mice also had a similar decrease in Factor 8-positive microvessel density. The vasoreactivity of wt compared to Gal-1-/-was tested in vivo and using isolated perfused lungs with acute hypoxia challenge. Acute hypoxia caused a significant increase in RVP of both wt and GAL-1-/-, however the response of the gal-1-/- was greater. These results suggest that Gal-1 influences the contractile response to hypoxia and subsequent remodeling during hy;poxia induced PH which influences disease progression.
