Angiopoietin-2 secretion by endothelial cell exosomes: regulation by the phosphatidylinositol 3-kinase (PI3K)/Akt/endothelial nitric oxide synthase (eNOS) and syndecan-4/syntenin pathways.
Angiopoietin-2 (Ang2) is an extracellular protein and one of the principal ligands of Tie2 receptor that is involved in the regulation of vascular integrity, quiescence, and inflammation. The mode of secretion of Ang2 has never been established, however. Here, we provide evidence that Ang2 is secreted from endothelial cells via exosomes and that this process is inhibited by the PI3K/Akt/endothelial nitric oxide synthase (eNOS) signaling pathway, whereas it is positively regulated by the syndecan-4/syntenin pathway. Vascular defects in Akt1 null mice arise, in part, because of excessive Ang2 secretion and can be rescued by the syndecan-4 knock-out that reduces extracellular Ang2 levels. This novel mechanism connects three critical signaling pathways: angiopoietin/Tie2, PI3K/Akt/eNOS, and syndecan/syntenin, which play important roles in vascular growth and stabilization.
From the Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine.
Rong
R
Ju
Zhen W
ZW
Zhuang
Jiasheng
J
Zhang
Anthony A
AA
Lanahan
Themis
T
Kyriakides
William C
WC
Sessa
Michael
M
Simons
D042702:Angiopoietin-2 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D055354:Exosomes / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D053671:Syndecan-4 / Q000235:genetics / Q000378:metabolism*; D053676:Syntenins / Q000235:genetics / Q000378:metabolism*
D042702:Angiopoietin-2; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D053676:Syntenins; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt
Endothelial Cell; Endothelium; Exocytosis; Exosomes; Vascular Biology