Soluble Guanylate Cyclase-α1 Deficiency Selectively Inhibits the Pulmonary Vasodilator Response to Nitric Oxide and Increases the Pulmonary Vascular Remodeling Response to Chronic Hypoxia

Abstract

Background— Nitric oxide (NO) activates soluble guanylate cyclase (sGC), a heterodimer composed of α- and β-subunits, to produce cGMP. NO reduces pulmonary vascular remodeling, but the role of sGC in vascular responses to acute and chronic hypoxia remains incompletely elucidated. We therefore studied pulmonary vascular responses to acute and chronic hypoxia in wild-type (WT) mice and mice with a nonfunctional α1-subunit (sGCα1 −/− ). Methods and Results— sGCα1 −/− mice had significantly reduced lung sGC activity and vasodilator-stimulated phosphoprotein phosphorylation. Right ventricular systolic pressure did not differ between genotypes at baseline and increased similarly in WT (22±2 to 34±2 mm Hg) and sGCα1 −/− (23±2 to 34±1 mm Hg) mice in response to acute hypoxia. Inhaled NO (40 ppm) blunted the increase in right ventricular systolic pressure in WT mice (22±2 to 24±2 mm Hg, P <0.01 versus hypoxia without NO) but not in sGCα1 −/− mice (22±1 to 33±1 mm Hg) and was accompanied by a significant rise in lung cGMP content only in WT mice. In contrast, the NO-donor sodium nitroprusside (1.5 mg/kg) decreased systemic blood pressure similarly in awake WT and sGCα1 −/− mice as measured by telemetry (−37±2 versus −42±4 mm Hg). After 3 weeks of hypoxia, the increases in right ventricular systolic pressure, right ventricular hypertrophy, and muscularization of intra-acinar pulmonary vessels were 43%, 135%, and 46% greater, respectively, in sGCα1 −/− than in WT mice ( P <0.01). Increased remodeling in sGCα1 −/− mice was associated with an increased frequency of 5′-bromo-deoxyuridine–positive vessels after 1 and 3 weeks ( P <0.01 versus WT). Conclusions— Deficiency of sGCα1 does not alter hypoxic pulmonary vasoconstriction. sGCα1 is essential for NO-mediated pulmonary vasodilation and limits chronic hypoxia-induced pulmonary vascular remodeling.