TY - JOUR
T1 - Alterations in TGF-β1 expression in lambs with increased pulmonary blood flow and pulmonary hypertension
AU - Mata-Greenwood, Eugenia
AU - Meyrick, Barbara
AU - Steinhorn, Robin H.
AU - Fineman, Jeffrey R.
AU - Black, Stephen M.
N1 - Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2003/7/1
Y1 - 2003/7/1
N2 - 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-β1 in this vascular remodeling, we investigated vascular changes in expression and localization of TGF-β1 and its receptors TβRI, ALK-1, and TβRII in lungs of shunted and control lambs at 1 day and 1, 4, and 8 wk of life. Western blots demonstrated that TGF-β1 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 TβRI was decreased at 4 wk of age (P < 0.05). Immunohistochemistry demonstrated shunts had increased TGF-β1 and TβRI expression in smooth muscle layer and increased TGF-β1 and ALK-1 in endothelium of small pulmonary arteries at 1 and 4 wk of age. Moreover, TβRI 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-β1 signaling, producing imbalance between pro- and antiangiogenic signaling that may be important in vascular remodeling in shunted lambs.
AB - 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-β1 in this vascular remodeling, we investigated vascular changes in expression and localization of TGF-β1 and its receptors TβRI, ALK-1, and TβRII in lungs of shunted and control lambs at 1 day and 1, 4, and 8 wk of life. Western blots demonstrated that TGF-β1 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 TβRI was decreased at 4 wk of age (P < 0.05). Immunohistochemistry demonstrated shunts had increased TGF-β1 and TβRI expression in smooth muscle layer and increased TGF-β1 and ALK-1 in endothelium of small pulmonary arteries at 1 and 4 wk of age. Moreover, TβRI 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-β1 signaling, producing imbalance between pro- and antiangiogenic signaling that may be important in vascular remodeling in shunted lambs.
KW - Shunted lambs
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U2 - 10.1152/ajplung.00171.2002
DO - 10.1152/ajplung.00171.2002
M3 - Article
C2 - 12665463
AN - SCOPUS:0038651033
SN - 1040-0605
VL - 285
SP - L209-L221
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 1 29-1
ER -