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1 EXPRESSION IN LAMBS WITH INCREASED PULMONARY BLOOD FLOW AND PULMONARY HYPERTENSION
1 Department of Pediatrics, Northwestern University, Chicago, IL, USA
2 Department of Pathology, Vanderbilt University Medical Center, Nashville, TN, USA
3 Department of Pediatrics, University of California San Francisco, San Francisco, CA, USA
4 Department of Pediatrics, Northwestern University, Chicago, IL, USA; Department of Molecular Pharmacology, Northwestern University, Chicago, IL, USA
* To whom correspondence should be addressed. E-mail: steveblack{at}northwestern.edu.
The mechanisms responsible for pulmonary vascular remodeling in association with increased pulmonary blood flow secondary to congenital heart disease remain unclear. We have developed a lamb model of congenital heart disease and increased pulmonary blood flow utilizing an in utero placed aortopulmonary vascular graft (shunt lambs). Morphometric analysis of barium-injected pulmonary arteries indicated that by 4-weeks of age, shunt lambs had twice the pulmonary arterial density of age-matched controls (P<0.05) and their pulmonary vessels showed increased muscularization and medial thickness at both 4- and 8-weeks of age (P<0.05). To determine the potential role of TGF-
1 in this vascular remodeling, we then investigated vascular changes in expression and localization of TGF-1 and its receptors TRI, ALK-1, and TRII in the lungs of shunted and age matched control lambs at 1 day, 1-, 4-, and 8-weeks of life. Western blots demonstrated that TGF-1 and ALK-1 expression were elevated in the shunt as compared to control lambs at 1- and 4-weeks of age (P<0.05). In contrast, the anti-angiogenic signaling receptor, TRI, was decreased at 4 wks of age (P<0.05). Immunohistochemistry demonstrated that, compared to controls, shunt lambs have increased TGF-1 and TRI expression in the smooth muscle layer, and increased TGF-1 and ALK-1 in the endothelium of small pulmonary arteries (<200 um) at 1 and 4-weeks of age. Moreover, TRI expression was significantly reduced in the endothelium of pulmonary arteries in the shunt at 1 and 4-weeks. Our data suggest that increased pulmonary blood flow and/or pressure dysregulates TGF-1 signaling by producing an imbalance between pro- and anti-angiogenic type I signaling receptors and that these effects are likely to be important in the development of vascular remodeling in the shunt model.
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