Soluble guanylate cyclase-α1 deficiency selectively inhibits the pulmonary vasodilator response to nitric oxide and increases the pulmonary vascular remodeling response to chronic hypoxia

Background - Nitric oxide ( NO) activates soluble guanylate cyclase (sGC), a heterodimer composed of alpha- and beta-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 alpha 1-subunit (sGC alpha 1(-/-)). Methods and Results - sGC alpha 1(-/-) 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 sGC alpha 1(-/-) (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 sGC alpha 1(-/-) 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 sGC alpha 1(-/-) 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 sGC alpha 1(-/-) than in WT mice (P < 0.01). Increased remodeling in sGC alpha 1(-/-) 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 sGC alpha 1 does not alter hypoxic pulmonary vasoconstriction. sGC alpha 1 is essential for NO-mediated pulmonary vasodilation and limits chronic hypoxia-induced pulmonary vascular remodeling.