Angiopoietin-2 Is Critical for Cytokine-Induced Vascular Leakage. e70459

• Published in: PloS one Vol. 8; no. 8
• Main Authors: Benest, Andrew V, Kruse, Karoline, Savant, Soniya, Thomas, Markus, Laib, Anna M, Loos, Elias K, Fiedler, Ulrike, Augustin, Hellmut G
• Format: Journal Article
• Language: English
• Published: 01.08.2013
• Subjects: Adenovirus; Autocrine signalling
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0070459

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.