Positive signaling feedback between VEGFR2 and Rap1b modulates EC responses to VEGF stimulation: a model. Rap1b acts upstream from VEGFR2 by regulating the activity of integrin α_vβ₃ and thus feeding into integrin α_vβ₃ signaling to VEGFR2. There is a reciprocal up-regulation of Rap1b and integrin β3 in the absence of either protein (Figure 3E and supplemental Figure 5B), further suggesting the existence of a feedback mechanism between the two proteins. Because inhibition of Rap1b in integrin β₃^−/− ECs leads to a further inhibition of VEGFR2 activation, other mediators of Rap1b regulation of VEGFR2 exist beside integrin β₃, however, they do not involve integrin α5β1. Rap1b also acts downstream from VEGFR2, as it becomes rapidly and transiently activated by VEGF.¹⁸  This creates a positive signaling feedback between Rap1b and VEGFR2 which promotes VEGF-induced blood vessel formation in vivo and EC responses in vitro; responses that are inhibited in mouse Rap1b-ECKO, zebrafish rap1b morphants and Rap1b^−/− ECs, respectively.