Abstract
Genetic experiments (loss-of-function and gain-of-function) have established the role of Angiopoietin/Tie ligand/receptor tyrosine kinase system as a regulator of vessel maturation and quiescence. Angiopoietin-2 (Ang-2) acts on Tie2-expressing resting endothelial cells as an antagonistic ligand to negatively interfere with the vessel stabilizing effects of constitutive Ang-1/Tie-2 signaling. Ang-2 thereby controls the vascular response to inflammation-inducing as well as angiogenesis-inducing cytokines. This study was aimed at assessing the role of Ang-2 as an autocrine (i.e. endothelial-derived) regulator of rapid vascular responses (within minutes) caused by permeability-inducing agents. Employing two independent in vivo assays to quantitatively assess vascular leakage (tracheal microsphere assay, 1–5 min and Miles assay, 20 min), the immediate vascular response to histamine, bradykinin and VEGF was analyzed in Ang-2-deficient (Ang-2−/−) mice. In comparison to the wild type control mice, the Ang2−/− mice demonstrated a significantly attenuated response. The Ang-2−/− phenotype was rescued by systemic administration (paracrine) of an adenovirus encoding Ang-2. Furthermore, cytokine-induced intracellular calcium influx was impaired in Ang-2−/− endothelioma cells, consistent with reduced phospholipase activation in vivo. Additionally, recombinant human Ang-2 (rhAng-2) alone was unable to induce vascular leakage. In summary, we report here in a definite genetic setting that Ang-2 is critical for multiple vascular permeability-inducing cytokines.
Highlights
A combination of sprouting angiogenesis-initiating cytokines, vascular guidance molecules and regulators of vessel maturation coordinate the growth of new blood vessels
An attenuated dose dependency was recorded in Ang22/2 mice, and significantly reduced microsphere accumulation was recorded compared to wild type (WT) responses (Fig. 2A, B, p,0.05, 12.5 mg and 62.5 mg histamine, p,0.01 312.5 mg histamine)
Loss of Ang-2 results in reduced PLCc2 activation From a range of potential effectors of calcium signaling, we demonstrated that histamine increased the activation of PLC2c at Tyrosine1217 (Fig. 8A, B, p,0.05) in WT mice
Summary
A combination of sprouting angiogenesis-initiating cytokines, vascular guidance molecules and regulators of vessel maturation coordinate the growth of new blood vessels. The Angiopoietins (Angiopoietin-1 [Ang-1] and -2 [Ang-2]) have been identified as agonistic and antagonistic ligands, respectively, of the vascularspecific receptor tyrosine kinase Tie-2 controlling multiple vessel maturation-related signaling pathways [1,2,3]. Recent work suggests that Ang-2 acts as context-specific agonistic and antagonistic ligand of Tie-2 exerting agonistic effects on angiogenically activated endothelial cells and antagonistic effects on resting Tie-2-expressing cells [4,5,6]. It is produced by the endothelium and stored in Weibel-Palade bodies from where it can be rapidly released upon stimulation [7,8,9]. The rapid release from endothelial cells supports the hypothesis that Ang functions as dynamic modulator of endothelial Tie-2 activation that controls rapid vascular responses [10]
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