Significance Reducing vascular leakage and stabilizing the endothelium through activation of the angiopoietin (ANGPT)–TIE2 receptor tyrosine kinase pathway is a promising therapeutic strategy for vascular diseases. ANGPT2 is one of two major ligands for the TIE2 receptor. Uniquely, ANGPT2 possesses an agonistic role in lymphatic endothelium, but acts as a competitive antagonist in blood endothelium. The molecular basis for the opposing actions of ANGPT2 in these two vascular beds is poorly understood. Here we demonstrate that the absence of VEPTP expression in the lymphatic endothelium confers an agonist function of ANGPT2 on TIE2 receptor, but VEPTP expression in blood endothelium abrogates its activity. Our findings provide mechanistic insights needed to advance therapeutic targeting of this pathway.