Production of recombinant Ang-1 is technically challenging as Ang-1 is 'sticky' because of its high affinity for the extracellular matrix [165] . However, stable Ang-1 variants with improved receptor affinity have been engineered. A stable soluble Ang-1 variant has anti-permeability activity [165] . When injected intraperitoneally in mice, human recombinant Ang-1 can prevent LPS-induced lung hyperpermeability [80] . In diabetic mice, a stable Ang-1 derivative attenuated proteinuria and delayed renal failure [166] , and manipulating the Ang-1/Ang-2 ratio changed infarct size [167] . A more profound Ang-1 effect can be achieved by locally stimulating Ang-1 production. In experimental acute respiratory distress syndrome, transfected cells expressing Ang-1 reduced alveolar inflammation and leakage [130] . An adenovirus construct encoding Ang-1 protected mice from death in an LPS model, and Ang-1 gene therapy reduced acute lung injury in a rat model [21, 168, 169] . In hypertensive rats, a plasmid expressing a stable Ang-1 protein reduced blood pressure and end-organ damage [170] . If used in a disease with a limited duration, as critical illness should be, virus/plasmid-driven production of Ang-1 could easily be shut down when it is no longer needed.