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We have previously shown that TGF-1 and VEGF expression are increased in the smooth muscle cell (SMC) layer of the pulmonary vessels of lambs with pulmonary hypertension secondary to increased pulmonary blood flow. Further we found that TGF-1 expression increased prior to VEGF. Due to the increased blood flow in these lambs the SMC in the pulmonary vessels are exposed to increased levels of cyclic stretch. Thus, using primary cultures of pulmonary arterial SMCs (PASMCs) isolated from 4 week-old lambs, we investigated the role of cyclic stretch in the apparent coordinated regulation of TGF-1 and VEGF. Our results demonstrated that cyclic stretch induced a significant increase in VEGF expression both at the mRNA and protein preceded by an increase in expression and secretion of TGF-1 and an increase in reactive oxygen species (ROS) generation. In addition, a neutralizing TGF-1 antibody abolished the cyclic stretch-dependent increase in ROS and VEGF expression. Further, we found that cyclic stretch activated an NAD(P)H oxidase in a TGF-1 dependent manner that when inhibited abolished the cyclic stretch-dependent increase in VEGF expression. Our results indicate that cyclic stretch up-regulates VEGF expression via the TGF-1 dependent activation of NAD(P)H oxidase and increased generation of ROS.