Soluble guanylate cyclase-alpha1 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 alpha1-subunit (sGCalpha1-/-).


RESULTS
sGCalpha1-/- 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 sGCalpha1-/- (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 sGCalpha1-/- 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 sGCalpha1-/- 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 sGCalpha1-/- than in WT mice (P<0.01). Increased remodeling in sGCalpha1-/- 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 sGCalpha1 does not alter hypoxic pulmonary vasoconstriction. sGCalpha1 is essential for NO-mediated pulmonary vasodilation and limits chronic hypoxia-induced pulmonary vascular remodeling.
Center for Transgene Technology and Gene Therapy, VIB, Leuven, Belgium.
Pieter
P
Vermeersch
Emmanuel
E
Buys
Peter
P
Pokreisz
Glenn
G
Marsboom
Fumito
F
Ichinose
Patrick
P
Sips
Marijke
M
Pellens
Hilde
H
Gillijns
Marc
M
Swinnen
Amanda
A
Graveline
Desire
D
Collen
Mieke
M
Dewerchin
Peter
P
Brouckaert
Kenneth D
KD
Bloch
Stefan
S
Janssens
D000208:Acute Disease; D000818:Animals; D000963:Antimetabolites / Q000493:pharmacokinetics; D001794:Blood Pressure / Q000502:physiology; D001973:Bromodeoxyuridine / Q000493:pharmacokinetics; D002908:Chronic Disease; D006152:Cyclic GMP / Q000378:metabolism; D019281:Dimerization; D005260:Female; D006162:Guanylate Cyclase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000378:metabolism / Q000503:physiopathology*; D017380:Hypertrophy, Right Ventricular / Q000378:metabolism / Q000503:physiopathology; D000860:Hypoxia / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000378:metabolism*; D011651:Pulmonary Artery / Q000502:physiology; D011652:Pulmonary Circulation / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000502:physiology*; D016278:Ventricular Function, Right / Q000502:physiology
D000963:Antimetabolites; D018160:Receptors, Cytoplasmic and Nuclear; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D001973:Bromodeoxyuridine; D006152:Cyclic GMP