Endothelial-to-mesenchymal transition (EndMT) is greatly implicated in various cardiopulmonary diseases. Although TGF has been shown to be involved in inducing EndMT, its downstream mechanisms especially in relationship with Akt1, a key serine threonine kinase vastly involved in regulating endothelial homeostasis and its role in EndMT remain unknown. The objective of this project is to understand the Akt-mediated regulation of Endothelial-to-Mesenchymal Transition (EndMT) and its contributions to pulmonary vascular remodeling. Using lentiviral mediated Akt1 knock down and pharmacological inhibition of Akt1 in endothelial cells we showed that endothelial loss of Akt1 enhances VEGF induced vascular permeability in the short term while blocks the VEGF- and Ang1-induced barrier stability in the long term. TGF1 inhibits Akt in the long term while activating Src resulting in enhanced vascular permeability indicating the protective role of Akt1 in regulating endothelial barrier integrity. Endothelial loss of Akt1 results in increased expression of mesenchymal markers N-cadherin and SMA, and decreases the expression of endothelial markers eNOS via upregulation of mesenchymal transcription factor Snail. This is mediated by the upregulation of the most predominant EndMT inducing TGF isoform, TGF2 and its downstream pro-fibrotic Smad, Smad2/3. In Chronic Hypoxia and Hypoxia-SUGEN models, endothelial specific loss of Akt1 in tamoxifen-inducible VE-cad-CreAkt1 mice resulted in exacerbated hypoxia-induced vascular remodeling compared to that of their WT controls. Inhibition of -catenin using ICG-001 reversed the hypoxia- and hypoxia-SUGEN-induced-vascular remodeling. SUGEN (SU-5416), a selective VEGFR2 inhibitor induced irreversible vascular remodeling in mice via suppression of Akt1. Together these results demonstrate the involvement of Akt1 in regulating endothelial barrier and homeostasis and that loss of Akt1 results in increased vascular permeability and EndMT in vitro and vascular remodeling in vivo. Targeting nuclear localization of -catenin might be a potential therapeutic option to prevent excessive vascular remodeling in several cardio-pulmonary diseases such as COPD, PAH etc.