TY - JOUR
T1 - Akt is a major angiogenic mediator downstream of the Ang1/Tie2 signaling pathway
AU - DeBusk, Laura M.
AU - Hallahan, Dennis E.
AU - Lin, Pengnian Charles
N1 - Funding Information:
This work was supported in part by grants (CA87756 for P.C.L.) (CA88076-02, CA90949-03 and CA89674-03 for DEH) from National Cancer Institute, by the Vanderbilt-Ingram Cancer Center (CA68485), Vanderbilt In Vivo Imaging Center (CA86283), and Vanderbilt Diabetes Center (DK20593) to PCL. LMB received training grant support from NCI.
PY - 2004/8/1
Y1 - 2004/8/1
N2 - Tie2 and VEGF receptors (VEGFRs) are tyrosine kinases that play essential roles in angiogenesis. Activation of both receptors leads to the activation of Akt, an important mediator of cell survival and cell motility. In this study, we compared the role of Akt in Tie2-mediated versus VEGF-mediated endothelial cell (EC) survival and EC sprouting. Our data show that Akt is required and sufficient to mediate Ang1-induced EC survival in response to growth factor depletion. Blocking Akt function abolishes angiopoietin 1 (Ang1), a ligand for Tie2, mediated EC survival, and activating Akt rescues a Tie2 blockade-induced EC apoptosis. In contrast, activating Akt rescues EC apoptosis induced by a VEGF blockade, but interestingly, blocking Akt function has no effects on VEGF-induced EC survival, demonstrating that Akt is sufficient but not required for VEGF-mediated EC survival. In addition, we show that both Ang1 and VEGF induce EC sprouting in a three-dimensional collagen gel, which depends on the activation of Akt. Blocking Akt action inhibited EC sprouting induced by Ang1 or VEGF. Therefore, the data show that Akt is the primary mediator of Ang1-induced EC survival while multiple pathways are involved downstream of VEGF responsible for EC survival. However, Akt is required and sufficient to mediate the EC sprouting induced by both Ang1 and VEGF.
AB - Tie2 and VEGF receptors (VEGFRs) are tyrosine kinases that play essential roles in angiogenesis. Activation of both receptors leads to the activation of Akt, an important mediator of cell survival and cell motility. In this study, we compared the role of Akt in Tie2-mediated versus VEGF-mediated endothelial cell (EC) survival and EC sprouting. Our data show that Akt is required and sufficient to mediate Ang1-induced EC survival in response to growth factor depletion. Blocking Akt function abolishes angiopoietin 1 (Ang1), a ligand for Tie2, mediated EC survival, and activating Akt rescues a Tie2 blockade-induced EC apoptosis. In contrast, activating Akt rescues EC apoptosis induced by a VEGF blockade, but interestingly, blocking Akt function has no effects on VEGF-induced EC survival, demonstrating that Akt is sufficient but not required for VEGF-mediated EC survival. In addition, we show that both Ang1 and VEGF induce EC sprouting in a three-dimensional collagen gel, which depends on the activation of Akt. Blocking Akt action inhibited EC sprouting induced by Ang1 or VEGF. Therefore, the data show that Akt is the primary mediator of Ang1-induced EC survival while multiple pathways are involved downstream of VEGF responsible for EC survival. However, Akt is required and sufficient to mediate the EC sprouting induced by both Ang1 and VEGF.
KW - Akt
KW - Angiopoietin
KW - Apoptosis
KW - Endothelial cell
KW - Tie2
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=3042702886&partnerID=8YFLogxK
U2 - 10.1016/j.yexcr.2004.04.013
DO - 10.1016/j.yexcr.2004.04.013
M3 - Article
C2 - 15242771
AN - SCOPUS:3042702886
SN - 0014-4827
VL - 298
SP - 167
EP - 177
JO - Experimental Cell Research
JF - Experimental Cell Research
IS - 1
ER -