Approximately 1% of children are born with congenital heart disease (CHD), with half requiring medical and/or surgical treatment. Although survival for these children has improved, they continue to suffer morbidity and late mortality, in part, because of the abnormal structural development of the pulmonary circulation, which varies depending on the amount of pulmonary blood flow. With increased pulmonary blood flow, there is increased pulmonary artery size, medial smooth muscle hypertrophy, and extension of muscle into non-muscular pulmonary arteries. This abnormal development is due, at least in part, to the pulmonary circulation being exposed to increased levels of fluid shear stress. Little is known about the mechanisms transducing this biomechanical force into alterations in pulmonary vascular growth. Our recent in vivo evidence implicates imbalances in the expression of both transforming growth factor-beta 1 (TGF-(31) and vascular endothelial growth factor (VEGF) as important mediators in this process. The overall hypothesis we will test in this proposal is that the vascular remodeling in CHD with increased pulmonary blood flow, is due, at least in part, to a shear stress dependent increase in VEGF expression mediated by increased activation of TGF-b1. In addition, we will test the hypothesis that nitric oxide (NO) plays an important role linking the activation of TGF-b1 with increased VEGF expression. To test these hypotheses we will elucidate the mechanisms by which: (1) TGF-b1 activation is regulated in vascular cultures exposed to shear stress; (2) Determine if this signaling pathway is recapitulated in vivo in our lamb model of CHD with increased pulmonary blood flow; and (3) NO-signaling regulates TGF-b1 activation and determine if chronic NOS inhibition in vivo will decrease TGF-b1/VEGF signaling and reduce the vascular remodeling observed in our model of CHD with increased pulmonary blood flow. The information garnered from these studies will elucidate the mechanisms by which biomechanical forces regulate the TGF-b1/VEGF axis and should prove to be significant in developing new treatment strategies for children with CHD. ? ? ?
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