['Therapeutic angiogenesis requires an understanding of how growth factors such as vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) result in physiological neovascularization. This study determined the physiological mechanism by which adenoviral delivery of growth factor combinations alter vascular phenotype and functionality.', 'Adenovirus-mediated gene transfer into the adjacent fat pad of the rat mesentery was used to characterize induction of angiogenesis by VEGF and Ang-1, in a model that permitted a detailed examination of the neovessel phenotype.', 'Ang-1 combined with VEGF resulted in a distinct vascular phenotype from either factor alone. Microvascular perfusion was significantly enhanced in all groups, but VEGF produced short, narrow, highly branched and sprouting vessels, with normal pericyte coverage. Ang-1 induced broader, longer neovessels, with no increase in branching or sprouting, yet a significantly higher pericyte ensheathment. Combination of Ang-1 and VEGF generated a significantly higher degree of functionally perfused, larger, less branched, and more mature microvessels, resulting from increased efficiency of sprout to vessel formation. Ang-1 and VEGF also caused differential effects on larger compared with smaller blood vessels, a finding reproduced in vitro.'] Do vEGF and angiopoietin-1 stimulate different angiogenic phenotypes that combine to enhance functional neovascularization in adult tissue?