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1 expression in lambs with increased pulmonary blood flow and pulmonary hypertension
Departments of 1Pediatrics and 4Molecular Pharmacology, Northwestern University, Chicago, Illinois 60611-3008; 2Department of Pathology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2650; and 3Department of Pediatrics, University of California San Francisco, San Francisco, California 94143-0106
Submitted 3 June 2002 ; accepted in final form 25 March 2003
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-
1 in this vascular
remodeling, we investigated vascular changes in expression and localization of
TGF-1 and its receptors TRI, ALK-1, and TRII in lungs of
shunted and control lambs at 1 day and 1, 4, and 8 wk of life. Western blots
demonstrated that TGF-1 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 TRI was decreased at 4
wk of age (P < 0.05). Immunohistochemistry demonstrated shunts had
increased TGF-1 and TRI expression in smooth muscle layer and
increased TGF-1 and ALK-1 in endothelium of small pulmonary arteries at
1 and 4 wk of age. Moreover, TRI 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-1 signaling,
producing imbalance between pro- and antiangiogenic signaling that may be
important in vascular remodeling in shunted lambs.
shunted lambs
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