ANGPT1Tie2

ANGPT1Tie2 refers to the signaling axis between angiopoietin-1 (ANGPT1), a secreted growth factor, and the Tie2 receptor tyrosine kinase (TEK) on endothelial cells. ANGPT1 binds to and activates Tie2, promoting receptor phosphorylation and initiating downstream signaling that supports vascular stability and quiescence.

Mechanistically, ANGPT1-Tie2 signaling enhances endothelial cell survival, maintains junctional integrity, and reduces vascular permeability. Key pathways include PI3K-AKT signaling, which promotes cell survival and barrier function, and downstream effects that strengthen adherens junctions such as VE-cadherin. The activity of Tie2 is modulated by phosphatases such as VE-PTP, which can dampen signaling. The axis counterbalances disruptive cues from inflammatory mediators and angiogenic stimuli, contributing to vessel maturation and stabilization.

Physiologically, ANGPT1-Tie2 signaling is essential during vascular development and in adult tissues to preserve vessel integrity, regulate permeability, and limit inflammatory extravasation. It works in concert with other angiogenic pathways to ensure proper remodeling and maintenance of the vascular network. Dysregulation of this axis can contribute to vascular instability and edema in various disease states.

In disease, reduced ANGPT1-Tie2 signaling is associated with leaky vasculature seen in sepsis, acute respiratory distress syndrome, and diabetic retinopathy, while ANGPT2 can antagonize or contextually modulate Tie2 activity, promoting vessel destabilization in inflammatory and tumor environments. Consequently, therapeutics that enhance ANGPT1-Tie2 signaling or inhibit ANGPT2 are under investigation, including Tie2 agonists and ANGPT2 antagonists, with mixed clinical results to date.