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.

Disruption of lineage specification in adult pulmonary mesenchymal progenitor cells promotes microvascular dysfunction

“…Vascular permeability in the lungs was quantitated using an AngioSense 750EX Fluorescent Imaging Agent (PerkinElmer) with spectroscopic imaging in a LI-COR Pearl Impulse Small Animal Imager (97). Elevated pulmonary artery pressure was documented indirectly by the measurement of RVSP and microvascular morphometry (98). The average interalveolar distance was assessed by quantification of MLI in lungs inflated with agarose under constant temperature and pressure as described previously (99,100).…”

ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling

“…Mice were euthanized between 14 and 21 days following bleomycin treatment (n ϭ 5-7 per group). Associated PH was documented by measurement of right ventricular systolic pressure (RVSP) as previously described (16,94). Five independent experiments were pooled for the hemodynamic measurements.…”

Influence of stress on extracellular matrix and integrin biology

“…Hypoxia also facilitates the accumulation of syndecan-4 in lung cancer cells (Koike et al, 2004). Hypoxia stimulates the production of galectin-1, a lactose-binding lectin, which enhances cell-to-ECM adhesion and contributes through this mechanism to hypoxia-induced pulmonary hypertension in mice (Case et al, 2007). Hypoxia facilitates the production of fibronectin in brain capillaries, in parallel with overexpression of integrin a5b1 (Milner et al, 2008).…”