Abstract
The angiopoietins Ang-1 and Ang-2 have been identified as ligands of the endothelial receptor tyrosine kinase Tie-2, which controls vascular assembly and endothelial quiescence. The largely complementary phenotypes of Ang-1-deficient mice and Ang-2-overexpressing mice have led to an antagonistic model in which Ang-1 acts as Tie-2-activating agonist and Ang-2 acts as a Tie-2-inhibiting antagonist. To date, no mechanistic equivalent of the antagonistic Ang-1/Ang-2 model has been established and the mechanisms of Ang-2 function in particular remain mysterious. We have studied the effector functions of Ang-1 and Ang-2 on quiescent endothelial cells using a three-dimensional co-culture model of endothelial cells and smooth-muscle cells. Endothelial-cell monolayer integrity in this model is dependent on Tie-2 signaling, as evidenced by detaching endothelial cells following exposure to the small molecular weight Tie-2 inhibitor A-422885.66, which cannot be overcome by exogenous Ang-1. Accordingly, exogenous Ang-2 rapidly destabilizes the endothelial layer, which can be observed within 30-60 minutes and leads to prominent endothelial-cell detachment within 4 hours. Exogenous Ang-2-mediated endothelial-cell detachment can be rescued by Ang-1, soluble Tie-2 and vascular endothelial growth factor. Similar findings were obtained in an umbilical-vein explant model. Ang-2 is mainly produced by endothelial cells and therefore acts primarily in an autocrine manner. Thus, stimulated release of endogenous Ang-2 or overexpression of Ang-2 in endothelial cells perturbs co-culture spheroid integrity, which can be rescued by exogenous Ang-1 and vascular endothelial growth factor. However, autocrine Ang-2-mediated endothelial-cell detachment cannot be blocked by soluble Tie-2. Taken together, the data demonstrate for the first time the antagonistic Ang-1/Ang-2 concept in a defined cellular model and identify Ang-2 as a rapidly acting autocrine regulator of the endothelium that acts through an internal autocrine loop mechanism.
Highlights
Angiogenesis, the formation of blood vessels from pre-existing vessels, is controlled by a hierarchically structured signaling cascade of endothelial-cell- expressed receptor tyrosine kinases
The vascular endothelial growth factor (VEGF)/VEGF-receptor (VEGFR) system acts as a master switch of angiogenesis induction, orchestrating early events of the angiogenic cascade, such as directional sprouting and endothelial cell proliferation, indicated by the early embryonic lethality of VEGF- or VEGFR-deficient mice (Carmeliet, 2003)
Bidirectional signaling through ephrin-B receptors (EphB) and their corresponding EphB ligands transduces propulsive and repulsive signals on angiogenic endothelial cells controlling arteriovenous differentiation and vascular network formation (Augustin and Reiss, 2003)
Summary
Angiogenesis, the formation of blood vessels from pre-existing vessels, is controlled by a hierarchically structured signaling cascade of endothelial-cell- expressed receptor tyrosine kinases. Angiopoietin-1 (Ang-1) has been identified as the agonistic ligand of Tie-2 (Suri et al, 1996) It regulates endothelialcell survival and blood-vessel maturation (Suri et al, 1996). Low-level constitutive Tie-2 activation might be required in the adult to maintain the mature quiescent phenotype of the resting vascular endothelium (Wong et al, 1997). According to these findings, functional knockdown of Tie-2 has recently been shown to cause endothelial-cell apoptosis by decreasing Akt signaling (Niu et al, 2004). Ang-1 is produced by many cell types, acts in a paracrine manner on endothelial cells and has been described as a transcriptionally regulated molecule in some tumors (Stratmann et al, 1998; Sugimachi et al, 2003)
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