Genetic disruption of atrial natriuretic peptide causes pulmonary hypertension in normoxic and hypoxic mice

To determine whether atrial natriuretic peptide (ANP) plays a physiological role in modulating pulmonary hypertensive responses, we studied mice with gene-targeted disruption of the ANP gene under normoxic and chronically hyp oxic conditions. Right ventricular peak pressure (RVPP), right ventricle we ight- and left ventricle plus septum weight-to-body weight ratios [RV/BW an d (LV+S)/BW, respectively], and muscularization of pulmonary vessels were m easured in wild-type mice (+/+) and in mice heterozygous (+/-) and homozygo us (-/-) for a disrupted proANP gene after 3 wk of normoxia or hypobaric hy poxia (0.5 atm). Under normoxic conditions, homozygous mutants had higher R VPP (22 +/- 2 vs. 15 +/- 1 mmHg; P < 0.05) than wild-type mice and greater RV/BW (1.22 +/- 0.08 vs. 0.94 +/- 0.07 and 0.76 +/- 0.04 mg/g; P < 0.05) an d (LV+S)/BW (4.74 +/- 0.42 vs. 3.53 +/- 0.14 and 3.18 +/- 0.18 mg/g; P < 0. 05) than heterozygous or wild-type mice, respectively. Three weeks of hypox ia increased RVPP in heterozygous and wild-type mice and increased RV/BW an d RV/(LV+S) in all genotypes compared with their normoxic control animals b ut had no effect on (LV+S)/BW. After 3 wk of hypoxia, homozygous mutants ha d higher RVPP (29 +/- 3 vs. 23 +/- 1 and 22 +/- 2 mmHg; P < 0.05), RV/BW (2 .03 +/- 0.14 vs. 1.46 +/- 0.04 and 1.33 +/- 0.08 mg/g; P < 0.05), and (LV+S )/BW (4.76 +/- 0.23 vs. 3.82 +/- 0.09 and 3.44 +/- 0.14 mg/g; P < 0.05) tha n heterozygous or wild-type mice, respectively. The percent muscularization of peripheral pulmonary vessels was greater in homozygous mutants than tha t in heterozygous or wild-type mice under both normoxic and hypoxic conditi ons. We conclude that endogenous ANP plays a physiological role in modulati ng pulmonary arterial pressure, cardiac hypertrophy, and pulmonary vascular remodeling under normoxic and hypoxic conditions.