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

Pieter Vermeersch, Emmanuel Buys, Peter Pokreisz, Glenn Marsboom, Fumito Ichinose, Patrick Sips (UGent) , Marijke Pellens, Hilde Gillijns, Marc Swinnen, Amanda Graveline, et al.
(2007) CIRCULATION. 116(8). p.936-943
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Abstract
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.
Keywords
guanylate cyclase, nitric oxide, hypoxia, hypertension, pulmonary, remodeling, ARTERIAL-HYPERTENSION, SMOOTH-MUSCLE, CYCLASE, MICE, GENE, VASOCONSTRICTION, ACTIVATION, SILDENAFIL, LUNG, PHOSPHORYLATION

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MLA
Vermeersch, Pieter, et al. “Soluble Guanylate Cyclase-Α1 Deficiency Selectively Inhibits the Pulmonary Vasodilator Response to Nitric Oxide and Increases the Pulmonary Vascular Remodeling Response to Chronic Hypoxia.” CIRCULATION, vol. 116, no. 8, 2007, pp. 936–43, doi:10.1161/CIRCULATIONAHA.106.677245.
APA
Vermeersch, P., Buys, E., Pokreisz, P., Marsboom, G., Ichinose, F., Sips, P., … Janssens, S. (2007). Soluble guanylate cyclase-α1 deficiency selectively inhibits the pulmonary vasodilator response to nitric oxide and increases the pulmonary vascular remodeling response to chronic hypoxia. CIRCULATION, 116(8), 936–943. https://doi.org/10.1161/CIRCULATIONAHA.106.677245
Chicago author-date
Vermeersch, Pieter, Emmanuel Buys, Peter Pokreisz, Glenn Marsboom, Fumito Ichinose, Patrick Sips, Marijke Pellens, et al. 2007. “Soluble Guanylate Cyclase-Α1 Deficiency Selectively Inhibits the Pulmonary Vasodilator Response to Nitric Oxide and Increases the Pulmonary Vascular Remodeling Response to Chronic Hypoxia.” CIRCULATION 116 (8): 936–43. https://doi.org/10.1161/CIRCULATIONAHA.106.677245.
Chicago author-date (all authors)
Vermeersch, Pieter, Emmanuel Buys, Peter Pokreisz, Glenn Marsboom, Fumito Ichinose, Patrick Sips, Marijke Pellens, Hilde Gillijns, Marc Swinnen, Amanda Graveline, Desié Collen, Mieke Dewerchin, Peter Brouckaert, Kenneth D Bloch, and Stefan Janssens. 2007. “Soluble Guanylate Cyclase-Α1 Deficiency Selectively Inhibits the Pulmonary Vasodilator Response to Nitric Oxide and Increases the Pulmonary Vascular Remodeling Response to Chronic Hypoxia.” CIRCULATION 116 (8): 936–943. doi:10.1161/CIRCULATIONAHA.106.677245.
Vancouver
1.
Vermeersch P, Buys E, Pokreisz P, Marsboom G, Ichinose F, Sips P, et al. Soluble guanylate cyclase-α1 deficiency selectively inhibits the pulmonary vasodilator response to nitric oxide and increases the pulmonary vascular remodeling response to chronic hypoxia. CIRCULATION. 2007;116(8):936–43.
IEEE
[1]
P. Vermeersch et al., “Soluble guanylate cyclase-α1 deficiency selectively inhibits the pulmonary vasodilator response to nitric oxide and increases the pulmonary vascular remodeling response to chronic hypoxia,” CIRCULATION, vol. 116, no. 8, pp. 936–943, 2007.
@article{377613,
  abstract     = {{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.}},
  author       = {{Vermeersch, Pieter and Buys, Emmanuel and Pokreisz, Peter and Marsboom, Glenn and Ichinose, Fumito and Sips, Patrick and Pellens, Marijke and Gillijns, Hilde and Swinnen, Marc and Graveline, Amanda and Collen, Desié and Dewerchin, Mieke and Brouckaert, Peter and Bloch, Kenneth D and Janssens, Stefan}},
  issn         = {{0009-7322}},
  journal      = {{CIRCULATION}},
  keywords     = {{guanylate cyclase,nitric oxide,hypoxia,hypertension,pulmonary,remodeling,ARTERIAL-HYPERTENSION,SMOOTH-MUSCLE,CYCLASE,MICE,GENE,VASOCONSTRICTION,ACTIVATION,SILDENAFIL,LUNG,PHOSPHORYLATION}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{936--943}},
  title        = {{Soluble guanylate cyclase-α1 deficiency selectively inhibits the pulmonary vasodilator response to nitric oxide and increases the pulmonary vascular remodeling response to chronic hypoxia}},
  url          = {{http://doi.org/10.1161/CIRCULATIONAHA.106.677245}},
  volume       = {{116}},
  year         = {{2007}},
}
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