The Angiopoietin-Tie2 Pathway in Critical Illness

Abstract

Lethal features of sepsis and acute respiratory distress syndrome (ARDS) relate to the health of small blood vessels. For example, alveolar infiltration with proteinaceous fluid is often driven by breach of the microvascular barrier. Spontaneous thrombus formation within inflamed microvessels exacerbates organ ischemia, and in its final stages, erupts into overt disseminated intravascular coagulation. Disruption of an endothelial signaling axis, the Angiopoietin-Tie2 pathway, may mediate the abrupt transition from microvascular integrity to pathologic disruption. This review summarizes preclinical and clinical results that implicate the Tie2 pathway as a promising target to restore microvascular health in sepsis and ARDS.

Keywords: ARDS; Angiopoietin; Coagulation; Sepsis; Tie2; VE-PTP; Vascular leakage.

Figure 1:

A) Endothelial cell Tie2 signaling during quiescence. Tie2 receptors cluster together and engage tetramers of Angpt-1 which results in activation of the receptor in a trans configuration. Furthermore, Tie1 binding further potentiates Tie2 activation. Downstream activation of Tie2 results in increased barrier function. B) Endothelial cell Tie2 signaling during inflammation. Tie2 receptor binds Angpt-2 dimers resulting in dephosphorylation and FOXO1 migration to the nucleus resulting in translation of inflammatory mediations and additional Angpt-2.

Figure 2:

Tie2 regulation occurs through the above three mechanisms. Angpt-1 binding to Tie2 results in c-Cbl ubiquination and resulting trafficking to lysosomes for destruction. Angpt-1 binding to Tie2 results in internalization whereas Angpt-2 binding is only able to minimally internalize receptor. Both Angpt-1 and Angpt-2 are released from receptor after engagement. Finally, Angpt-2 and Angpt-1 engaged receptors are shed from endothelial cells by metalloproteinase resulting in decreased receptor pool available for receptor engagement.