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Transforming growth factor-β1 causes pulmonary microvascular endothelial cell apoptosis via ALK5

Vascular Research Laboratory, Providence Veterans Affairs Medical Center, Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island

Submitted 9 May 2008 ; accepted in final form 26 February 2009

We have previously shown that transforming growth factor (TGF)-β1 protected against main pulmonary artery endothelial cell (PAEC) apoptosis induced by serum deprivation and VEGF receptor blockade through a mechanism associated with ALK5-mediated Bcl-2 upregulation. In the current study, we investigated the effect of TGF-β1 on pulmonary microvascular endothelial cell (PMVEC) apoptosis. We found that, in contrast to the results seen in conduit PAEC, TGF-β1 caused apoptosis of PMVEC, an effect that was also dependent on ALK5 activity. We noted that non-SMAD signaling pathways did not play a role in TGF-β1-induced apoptosis. Both SMAD2 and SMAD1/5 were activated upon exposure to TGF-β1. TGF-β1-induced activation of SMAD2, but not SMAD1/5, was abolished by ALK5 inhibition, an effect that associated with prevention of TGF-β1-induced apoptosis. These results suggest that SMAD2 is important in TGF-β1-induced apoptosis of PMVEC. While caspase-12 activity was not altered, caspase-8 was activated by TGF-β1, an effect that correlated with a reduction of cFLIP protein levels. Additionally, TGF-β1 decreased Bcl-2 protein levels and induced cytochrome c cytosolic redistribution. These results suggest that TGF-β1 caused apoptosis of PMVEC likely through both caspase-8-dependent extrinsic pathway and mitochondria-mediated intrinsic pathway. We noted that inhibition of ALK5 attenuated serum deprivation-induced apoptosis, an effect that correlated with increased expression and activation of CREB and its potential target genes, Bcl-2 and cFLIP. These results suggest that CREB may be important in mediating apoptosis resistance of PMVEC upon ALK5 inhibition perhaps through upregulation of Bcl-2 and cFLIP. Finally, we noted that SMAD1/5 were activated upon ALK5 inhibition in the presence of low levels of TGF-β1, an effect associated with enhanced endothelial proliferation. We speculate that imbalance of ALK1 and ALK5 may contribute to the development of pulmonary artery hypertension.

ALK1; SMAD; Bcl-2; cFLIP; pulmonary artery hypertension