Early abnormalities of pulmonary vascular development in the Fawn-Hooded rat raised at Denver's altitude

The Fawn-Hooded rat (FHR) is a genetic strain that has been extensively stu died as a model of primary pulmonary hypertension in adult rats. Based on o ur recent observations that alveolar number and pulmonary arterial density are reduced in FHRs raised at Denver's altitude, we hypothesized that early abnormalities in pulmonary vascular development contribute to the progress ion of pulmonary hypertension in the FHR. We found that endothelial nitric oxide synthase (eNOS) protein content was lower in the lungs of fetal, 1- a nd 7-day-old, 3-week-old, and adult FHRs compared with that in the normal S prague-Dawley (SDR) and Fischer rat strains, all raised at Denver's altitud e. In contrast, lung expression of the endothelial proteins kinase insert d omain-containing receptor/fetal liver kinase-1 (KDR/Flk-1) and platelet end othelial cell adhesion molecule-1 (CD31) was not different between strains. Barium arteriograms showed that pulmonary arterial density was reduced in 3-week-old FHRs compared with SDRs. Perinatal treatment of FHRs with mild h yperbaria to simulate sealevel alveolar PO2 improved lung eNOS content and pulmonary vascular growth and reduced right ventricular hypertrophy. We con clude that the development of pulmonary hypertension in Denver-raised FHRs is characterized by reductions in lung eNOS expression and abnormal pulmona ry vascular growth during the fetal, neonatal, and postnatal periods.