Angiopoietin-2 functions as an autocrine protective factor in stressed endothelial cells

Abstract

Angiopoietin (Ang)-2, a context-dependent agonist͞antagonist for the vascular-specific Tie2 receptor, is highly expressed by endothelial cells at sites of normal and pathologic angiogenesis. One prevailing model suggests that in these settings, Ang-2 acts as an autocrine Tie2 blocker, inhibiting the stabilizing influence of the Tie2 activator Ang-1, thereby promoting vascular remodeling. However, the effects of endogenous Ang-2 on cells that are actively producing it have not been studied in detail. Here, we demonstrate that Ang-2 expression is rapidly induced in endothelial cells by the transcription factor FOXO1 after inhibition of the phosphatidylinositol 3-kinase͞Akt pathway. We employ RNAi and blocking antibodies to show that in this setting, Ang-2 unexpectedly functions as a Tie2 agonist, bolstering Akt activity so as to provide negative feedback on FOXO1-regulated transcription and apoptosis. In addition, we show that Ang-2, like Ang-1, activates Tie2͞Akt signaling in vivo, thereby inhibiting the expression of FOXO1 target genes. Consistent with a role for Ang-2 as a Tie2 activator, we demonstrate that Ang-2 inhibits vascular leak. Our data suggests a model in which Ang-2 expression is induced in stressed endothelial cells, where it acts as an autocrine Tie2 agonist and protective factor.

Cyclic tensile strain triggers a sequence of autocrine and paracrine signaling to regulate angiogenic sprouting in human vascular cells

“…However, recent studies demonstrate that there may exist a contextual role to the functions of Ang-2, because it serves in some instances to inhibit vascular leakage (51), whereas in other situations, it may function as a proinflammatory cytokine (52). Increased secretion of Ang-2 in response to biochemical stimulants has also been documented, supporting the suggestion (53) that Ang-2 function is more complex than initially identified (54).…”

Yes-associated protein regulates endothelial cell contact-mediated expression of angiopoietin-2

“…ANG-2, an autocrine factor that is released from active ECs, regulates angiogenesis in a pro-or anti-angiogenic manner, depending on cell context 11,13 . Because YAP is localized in the nucleus in loosely contacted ECs, which is a feature of relatively active ECs, we expected that YAP might regulate ANG-2.…”

“…ANG-2 was first identified as a natural antagonist of ANG-1/Tie-2 signalling in ECs 11 . However, subsequent studies report conflicting results demonstrating its pro-angiogenic activity in vitro or in vivo 12,13 . ANG-2 also sensitizes ECs to respond to inflammatory cytokines, such as tumour-necrosis factor-a, and thus enhances angiogenesis triggered by inflammation 14 .…”

VEGF-targeted cancer therapy strategies: current progress, hurdles and future prospects

“…Furthermore, newer molecular candidates, such as the angiopoietins, NOTCH or axon-guiding molecules should be studied in this context. Angiopoietin-1 and angiopoietin-2 bind to their cognate tyrosine kinase receptor TEK/TIE2 on endothelial cells, and modulate endothelial-cell survival and angiogenesis in a context-dependent manner [28,29]. Recently, the NOTCH family has been intensely studied because of their emerging role in tumor angiogenesis in close interrelation with VEGF [30][31][32].…”