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 studied as a model of primary pulmonary hypertension in adult rats. Based on our 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 progression of pulmonary hypertension in the FHR. We found that endothelial nitric oxide synthase (eNOS) protein content was lower in the lungs of fetal, 1- and 7-day-old, 3-week-old, and adult FHRs compared with that in the normal Sprague-Dawley (SDR) and Fischer rat strains, all raised at Denver's altitude. In contrast, lung expression of the endothelial proteins kinase insert domain-containing receptor/fetal liver kinase-1 (KDR/Flk-1) and platelet endothelial 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 hyperbaria to simulate sea-level alveolar PO(2) improved lung eNOS content and pulmonary vascular growth and reduced right ventricular hypertrophy. We conclude that the development of pulmonary hypertension in Denver-raised FHRs is characterized by reductions in lung eNOS expression and abnormal pulmonary vascular growth during the fetal, neonatal, and postnatal periods.
Le Cras
T D
TD
Pediatric Heart Lung Center, Department of Pediatrics, University of Colorado School of Medicine and The Children's Hospital, Denver, Colorado 80262, USA. Timothy.Lecras@uchsc.edu
Kim
D H
DH
Markham
N E
NE
Abman
A S
AS
D000531:Altitude; D000818:Animals; D001011:Aorta / Q000201:enzymology; D001274:Atmospheric Pressure; D015153:Blotting, Western; D001835:Body Weight; D006976:Hypertension, Pulmonary / Q000235:genetics; D008168:Lung / Q000002:abnormalities* / Q000098:blood supply* / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III; D009929:Organ Size; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D011652:Pulmonary Circulation / Q000235:genetics* / Q000502:physiology*; D051381:Rats; D011916:Rats, Inbred F344; D011919:Rats, Inbred Strains; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000096:biosynthesis; D017978:Receptors, Growth Factor / Q000096:biosynthesis; D040262:Receptors, Vascular Endothelial Growth Factor; D013045:Species Specificity
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017978:Receptors, Growth Factor; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D040262:Receptors, Vascular Endothelial Growth Factor