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Abstract
Slit proteins induce cytoskeletal remodeling through interaction with roundabout (Robo) receptors, regulating migration of neurons and nonneuronal cells, including leukocytes, tumor cells, and endothelium. The role of Slit2 in vascular remodeling, however, remains controversial, with reports of both pro- and antiangiogenic activity. We report here that cooperation between Slit2 and ephrin-A1 regulates a balance between the pro- and antiangiogenic functions of Slit2. While Slit2 promotes angiogenesis in culture and in vivo as a single agent, Slit2 potently inhibits angiogenic remodeling in the presence of ephrin-A1. Slit2 stimulates angiogenesis through mTORC2-dependent activation of Akt and Rac GTPase, the activities of which are inhibited in the presence of ephrin-A1. Activated Rac or Akt partially rescues vascular assembly and motility in costimulated endothelium. Taken together, these data suggest that Slit2 differentially regulates angiogenesis in the context of ephrin-A1, providing a plausible mechanism for the pro- versus antiangiogenic functions of Slit2. Our results suggest that the complex roles of Slit-Robo signaling in angiogenesis involve context-dependent mechanisms.
ACKNOWLEDGMENTS
We thank Carlos Arteaga and Mark Magnuson at Vanderbilt University for sharing the myr-Akt construct and floxed rictor mice, respectively. We thank Keunwook Lee at Vanderbilt University for assistance with experiments involving floxed rictor mice. We also thank Amanda Beauchamp and Waldemar Debinski at Wake Forest University School of Medicine for advice and protocols on analysis of soluble ephrin-A1.
This work was supported by a VA Merit Award through the Department of Veterans Affairs and NIH grants CA95004 and CA114301 to J. Chen and by NIH grant CA1179151 to D. M. Brantley-Sieders. Rebecca Cook is supported by NIH grant CA143126. Jane Y. Wu is supported by NIH grants CA114197 and CA107193 and by the James S. McDonnell Foundation. Mark Boothby is supported by NIH grant AI068149.
Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00667-10.