title: Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy.
abstract: High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins (P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work (P < 0.05 vs. control and ETX+vit D) and elastic potential energy (P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA (P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment.
authors.affiliation: Department of Pediatrics, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado; The Pediatric Heart Lung Center, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Erica
authors.initials: E
authors.lastname: Mandell
authors.affiliation: Department of Surgery, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado; The Pediatric Heart Lung Center, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado; The Laboratory for Fetal and Regenerative Biology; and.
authors.forename: Kyle N
authors.initials: KN
authors.lastname: Powers
authors.affiliation: Division of Cardiovascular Pulmonary Research, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Julie W
authors.initials: JW
authors.lastname: Harral
authors.affiliation: Department of Pediatrics, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado; The Pediatric Heart Lung Center, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Seedorf
authors.affiliation: Department of Bioengineering, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Kendall S
authors.initials: KS
authors.lastname: Hunter
authors.affiliation: Department of Pediatrics, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado; The Pediatric Heart Lung Center, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
authors.affiliation: Department of Surgery, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado; Department of Bioengineering, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado; The Pediatric Heart Lung Center, University of Colorado at Denver Anschutz Medical Campus, Aurora, Colorado; The Laboratory for Fetal and Regenerative Biology; and blair.dodson@ucdenver.edu.
authors.forename: R Blair
authors.initials: RB
authors.lastname: Dodson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D004549:Elastin / Q000378:metabolism; D004731:Endotoxins / Q000009:adverse effects*; D005260:Female; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012143:Respiratory Physiological Phenomena / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014807:Vitamin D / Q000008:administration & dosage*
chemical_list: D004731:Endotoxins; D014807:Vitamin D; D004549:Elastin
keywords: arterial stiffening; bronchopulmonary dysplasia; chorioamnionitis; extracellular matrix; vascular remodeling