Mechanisms of vessel remodeling are not yet fully understood. The purpose of this study is to identify proteins that regulate vascular remodeling in an ROP mouse model. Mice were treated with fluctuating oxygen levels and retinas sampled at the peak of vessel regression (PN12) or neovascularization (PN17) for comparative SWATH-MS proteomics using liquid chromatography-tandem mass spectrometry (LC-MS/MS). We further developed an endothelial cell culture ROP correlate to validate expression of target neovascular markers. 5191 proteins were identified in the retinas of which 498 showed significant changes in expression in elevated oxygen and 345 after a return to normoxia. 122 proteins were uniquely associated with vessel regression and 69 with neovascularization (FC>1.5; P<0.05). Of the latter set, 56 were detected in human retinal endothelial cells (HRECs) of which 42 showed altered expression in the HREC-ROP correlate and 23 regulated in the same direction as in the neovascular retinas. In functional analysis, HREC-specific proteins control angiogenesis-related processes including extracellular matrix remodeling, cell migration and adhesion, junction proteins and proliferation. RNA interference and transfection overexpression studies confirmed that VASP and ECH1, showing highest expression levels in hypoxic HRECs, promoted endothelial cell proliferation while SNX1 and CD109, showing lowest expression, inhibited their proliferation.