Fig. 8. Proposed model of the functional consequences of EC ephrinB2 and EphB4 signaling during guided migration (A) and capillary network formation (B). The model is based on the functional data summarized in this manuscript and takes into account published data on the repulsive guidance of ECs and neural crest cells by surrounding cells (Helbling et al., 2000; Krull et al., 1997; Oike et al., 2002; Wang and Anderson, 1997). Similar to guided nerve cell outgrowth, forward EphB4 signals may direct ECs in a repulsive manner upon activation by surrounding cells avoiding areas where ephrinB2 is expressed (guided migration, A, stop signal). The opposite, promotion of EC migration may occur if ephrinB2-expressing angiogenic ECs are activated by EphB4 (A, go signal). Additionally, these effects may segregate ECs from each other to limit cellular intermingling and control arterio-venous positioning of cells (network formation, B). Propulsive and repulsive EC forces during capillary morphogenesis indicate an arterio-venous push and pull situation that supports an artery-to-vein model of invasive angiogenesis.

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