title: Alterations in TGF-beta1 expression in lambs with increased pulmonary blood flow and pulmonary hypertension.
abstract: The mechanisms responsible for pulmonary vascular remodeling in congenital heart disease with increased pulmonary blood flow remain unclear. We developed a lamb model of congenital heart disease and increased pulmonary blood flow utilizing an in utero placed aortopulmonary vascular graft (shunted lambs). Morphometric analysis of barium-injected pulmonary arteries indicated that by 4 wk of age, shunts had twice the pulmonary arterial density of controls (P < 0.05), and their pulmonary vessels showed increased muscularization and medial thickness at both 4 and 8 wk of age (P < 0.05). To determine the potential role of TGF-beta1 in this vascular remodeling, we investigated vascular changes in expression and localization of TGF-beta1 and its receptors TbetaRI, ALK-1, and TbetaRII in lungs of shunted and control lambs at 1 day and 1, 4, and 8 wk of life. Western blots demonstrated that TGF-beta1 and ALK-1 expression was elevated in shunts compared with control at 1 and 4 wk of age (P < 0.05). In contrast, the antiangiogenic signaling receptor TbetaRI was decreased at 4 wk of age (P < 0.05). Immunohistochemistry demonstrated shunts had increased TGF-beta1 and TbetaRI expression in smooth muscle layer and increased TGF-beta1 and ALK-1 in endothelium of small pulmonary arteries at 1 and 4 wk of age. Moreover, TbetaRI expression was significantly reduced in endothelium of pulmonary arteries in the shunt at 1 and 4 wk. Our data suggest that increased pulmonary blood flow dysregulates TGF-beta1 signaling, producing imbalance between pro- and antiangiogenic signaling that may be important in vascular remodeling in shunted lambs.
authors.affiliation: Department of Pediatrics, Northwestern University, Chicago, Illinois 60611-3008, USA.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Mata-Greenwood
authors.forename: Barbara
authors.initials: B
authors.lastname: Meyrick
authors.forename: Robin H
authors.initials: RH
authors.lastname: Steinhorn
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Fineman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D005260:Female; D006976:Hypertension, Pulmonary / Q000473:pathology / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000473:pathology / Q000503:physiopathology; D011247:Pregnancy; D017346:Protein Serine-Threonine Kinases; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D011652:Pulmonary Circulation / Q000502:physiology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II