Backgrounds: Recently peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1慣), a master regulator of mitochondrial biogenesis and cellular energy metabolism, has been shown to control angiogenic process to fulfill oxygen and substrate requirements of the tissue. Though intact vascular barrier function is necessary for new vessels to supply sufficient oxygen and substrate to tissue, the role of PGC-1慣 in vascular barrier function has not been elucidated, yet. Here, we investigated the role of PGC-1慣 in regulating vascular permeability. Methods and Results: PGC-1慣 over-expression by adenoviral vector reduced vascular permeability and increased gaps in endothelial cells monolayer while PGC-1慣 knock-down by siRNA increased vascular permeability and decreased gaps in endothelial cell monolayer (Figure 1). This regulation of vascular permeability by PGC-1慣 over-expression was accompanied by reduction of angiopoietin-2 expression. PGC-1慣 over-expression decreased FOXO1a nuclear translocation and thereby reduced angiopoietin-2 mRNA expression. In vivo, local PGC-1慣 over-expression reduced vascular leakage at the inflamed ears of mice, as evidenced by both Evans blue dye and TRITC-dextran exclusion test (Figure 2). In addition, PGC-1慣 over-expression reduced vascular leakage during neovascularization in matrigel plug assay. Conclusions: PGC-1慣 regulates vascular permeability and expression of angiopoietin-2, a key regulator of vascular permeability, in endothelial cells. This result identifies PGC-1慣 as a new molecular regulator of tissue metabolic demand and supply.