The pulmonary circulation of homozygous of heterozygous eNOS-null mice is hyperresponsive to mild hypoxia

Acute hypoxic vasoconstriction and development of hypoxic pulmonary hyperte nsion (PHTN) are unique properties of the pulmonary circulation. The pulmon ary endothelium produces vasoactive factors, including nitric oxide (NO), t hat modify these phenomena. We tested the hypothesis that NO produced by en dothelial nitric oxide synthase (eNOS) modulates pulmonary vascular respons es to hypoxia using mice with targeted disruption of the eNOS gene (eNOS(-/ -)). Marked PHTN was found in eNOS(-/-) mice raised in mild hypoxia when co mpared with either controls or eNOS(-/-) mice raised in conditions simulati ng sea level. We found an approximate twofold increase in partially and ful ly muscularized distal pulmonary arteries in eNOS(-/-) mice compared with c ontrols. Consistent with vasoconstriction being the primary mechanism of PH TN, however, acute inhalation of 25 ppm NO resulted in normalization of RV pressure in eNOS(-/-) mice. In addition to studies of eNOS(-/-) mice, the d ose-effect of eNOS was tested using heterozygous eNOS(+/-) mice. Although t he lungs of eNOS(+/-) mice had 50% of normal eNOS protein, the response to hypoxia was indistinguishable from that of eNOS(-/-) mice. We conclude that eNOS-derived NO is an important modulator of the pulmonary vascular respon se to chronic hypoxia and that more than 50% of eNOS expression is required to maintain normal pulmonary vascular tone.