Dynamic decoding of VEGF signaling and coordinated control of multiple phenotypes by the Src-TEM4-YAP pathway

Responses of endothelial cells to elevated levels of vascular endothelial growth factor (VEGF), frequently accompanying local decrease in oxygen supply, include loosening of cell contacts, rearrangement of cells in vessel remodeling, and ultimately, angiogenic growth. How these complex processes, occurring on diverse time scales, are coordinated and how they are guided by a single key signaling input is still incompletely understood. Here, we show that the various phenotypic responses associated with VEGF signaling are controlled at different steps of a pathway involving sequential activation of Src, tumor endothelial marker 4 (TEM4), YAP, and components of pro-angiogenic Notch signaling. Notably, due to feedback regulation at different pathway levels, the functional outcomes are controlled by oscillations of the pathway components occurring on distinct time scales. Deeper pathway layers integrate faster upstream responses and control progressively slower phenotypic outcomes. This signal-decoding pathway organization can ensure a high degree of complexity in a vital physiological process. A record of this paper's transparent peer review process is included in the supplemental information.