Alterations in TGF-β1 expression in lambs with increased pulmonary blood flow and pulmonary hypertension

Eugenia Mata-Greenwood, Barbara Meyrick, Robin H Steinhorn, Jeffrey R. Fineman, Stephen M. Black

Research output: Contribution to journalArticle

58 Scopus citations

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-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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume285
Issue number1 29-1
StatePublished - Jul 1 2003
Externally publishedYes

Keywords

  • Shunted lambs

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Cell Biology
  • Physiology

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