Robo4-dependent Slit signaling stabilizes the vasculature during pathologic angiogenesis and cytokine storm.

PURPOSE OF REVIEW: The endothelium is bombarded with and must respond to multiple destabilizing proangiogenic and inflammatory cytokines. RECENT
FINDINGS: Endogenous cell signaling systems such as Roundabout (Robo)4-dependent Slit signaling are in place to help maintain homeostatic balance and prevent excessive destabilization. Upon Robo4 activation by Slit, paxillin is recruited to the cytoplasmic domain along with an ArfGAP known as GIT1. GIT1 recruitment results in inactivation of Arf6, a protein shown to regulate cadherin cell surface localization. Slit increases vascular endothelial-cadherin presentation at the cell surface and enhances vascular barrier function in the presence of inflammatory cytokines.
SUMMARY: Through harnessing Robo4-dependent Slit signaling, survival can be enhanced in mouse models of sepsis and avian flu infection. This effect is achieved by blunting the host vascular response to cytokines. Thus, vascular stabilizing programs should be investigated as potential therapeutics for infectious disease characterized by cytokine storm.