title: Chronic intrauterine pulmonary hypertension increases main pulmonary artery stiffness and adventitial remodeling in fetal sheep.
abstract: Persistent pulmonary hypertension of the newborn (PPHN) is a clinical syndrome that is characterized by high pulmonary vascular resistance due to changes in lung vascular growth, structure, and tone. PPHN has been primarily considered as a disease of the small pulmonary arteries (PA), but proximal vascular stiffness has been shown to be an important predictor of morbidity and mortality in other diseases associated with pulmonary hypertension (PH). The objective of this study is to characterize main PA (MPA) stiffness in experimental PPHN and to determine the relationship of altered biomechanics of the MPA with changes in extracellular matrix (ECM) content and orientation of collagen and elastin fibers. MPAs were isolated from control and PPHN fetal sheep model and were tested by planar biaxial testing to measure stiffness in circumferential and axial vessel orientations. Test specimens were fixed for histological assessments of the vascular wall ECM constituents collagen and elastin. MPAs from PPHN sheep had increased mechanical stiffness (P < 0.05) and altered ECM remodeling compared with control MPA. A constitutive mathematical model and histology demonstrated that PPHN vessels have a smaller contribution of elastin and a greater role for collagen fiber engagement compared with the control arteries. We conclude that exposure to chronic hemodynamic stress in late-gestation fetal sheep increases proximal PA stiffness and alters ECM remodeling. We speculate that proximal PA stiffness further contributes to increased right ventricular impedance in experimental PPHN, which contributes to abnormal transition of the pulmonary circulation at birth.
authors.affiliation: Pediatric Heart Lung Center, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado; Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado; Department of Bioengineering, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado; and blair.dodson@ucdenver.edu.
authors.forename: R Blair
authors.initials: RB
authors.lastname: Dodson
authors.affiliation: Department of Biomedical Engineering, Duke University, Durham, North Carolina.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Morgan
authors.affiliation: Pediatric Heart Lung Center, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado; Department of Pathology, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Csaba
authors.initials: C
authors.lastname: Galambos
authors.affiliation: Department of Bioengineering, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado; and.
authors.forename: Kendall S
authors.initials: KS
authors.lastname: Hunter
authors.affiliation: Pediatric Heart Lung Center, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado; Department of Pediatrics, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
mesh_terms: D063194:Adventitia / Q000473:pathology / Q000503:physiopathology*; D000818:Animals; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D004622:Embryo, Mammalian / Q000503:physiopathology; D005109:Extracellular Matrix / Q000473:pathology; D006439:Hemodynamics; D006801:Humans; D007231:Infant, Newborn; D008168:Lung / Q000473:pathology / Q000503:physiopathology; D010547:Persistent Fetal Circulation Syndrome / Q000473:pathology / Q000503:physiopathology*; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology*; D011652:Pulmonary Circulation; D012756:Sheep; D014655:Vascular Resistance / Q000502:physiology*; D059289:Vascular Stiffness
chemical_list: D003094:Collagen; D004549:Elastin
keywords: biomechanics; collagen; elastin; extracellular matrix; lung development; persistent pulmonary hypertension of the newborn