Abstract
The formation of endothelial lumen is fundamental to angiogenesis and essential to the oxygenation of hypoxic tissues. The molecular mechanism underlying this important process remains obscure. Here, we show that Akt activation by a Ras homolog, R-Ras, stabilizes the microtubule cytoskeleton in endothelial cells leading to endothelial lumenogenesis. The activation of Akt by the potent angiogenic factor VEGF-A does not strongly stabilize microtubules or sufficiently promote lumen formation, hence demonstrating a distinct role for the R-Ras-Akt axis. We show in mice that this pathway is important for the lumenization of new capillaries and microvessels developing in ischemic muscles to allow sufficient tissue reperfusion after ischemic injury. Our work identifies a role for Akt in lumenogenesis and the significance of the R-Ras-Akt signaling for the patency of regenerating blood vessels.
Highlights
The formation of endothelial lumen is fundamental to angiogenesis and essential to the oxygenation of hypoxic tissues
We first analyzed the effect of R-Ras on endothelial morphogenesis in vitro in a fibrin gel three-dimensional (3-D) culture of Endothelial cells (ECs), which recapitulates the sequential steps of angiogenesis, i.e., sprouting, branching, and lumen formation (Fig. 1a, b)
We found that Akt activation by R-Ras is a critical signaling event for the lumen formation during reparative angiogenesis
Summary
The formation of endothelial lumen is fundamental to angiogenesis and essential to the oxygenation of hypoxic tissues. The activation of Akt by the potent angiogenic factor VEGF-A does not strongly stabilize microtubules or sufficiently promote lumen formation, demonstrating a distinct role for the R-Ras-Akt axis. The vessel density of the ischemic muscles of the Akt1−/− mice was found comparable to that of the control normoxic muscles of wild-type mice This finding suggests that the Akt[1] deficiency compromised EC’s ability to proliferate and sprout, and significantly impaired the morphogenesis of the new vessels, making these vessels inadequate for supporting the reperfusion and reoxygenation of the ischemic tissues. R-Ras activates the PI3K-Akt but not Raf-Erk signaling[10], and this PI3K-Akt activation does not seem to participate in the canonical proangiogenic Akt signaling since the gain-of-function of R-Ras limits vessel sprouting, branching, EC migration, and permeability[11,12,18] This suggests that the Akt signaling elicited by R-Ras may have a distinct role in angiogenesis. The improved perfusion of these vessels may be due to the facilitation of proper endothelial morphogenesis
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
