Angiopoietins and Tie2 in vascular inflammation

Abstract

Purpose of review: As a subset of the organism-wide reaction to severe infection, the host vascular response has received increasing attention in recent years. The transformation that small blood vessels undergo to facilitate the clearance of pathogens may become harmful to the host if it occurs too broadly or if it is sustained too long. Adverse clinical manifestations of leaky and inflamed blood vessels include edema impairing the function of critical organs and circulatory shock.

Recent findings: The study suggests that this host vascular response may be both measurable and potentially targetable. Tie2 is a receptor tyrosine kinase (RTK) heavily enriched in the vascular endothelium whose tonic signaling actively maintains vascular quiescence. When Tie2 becomes inactivated, important molecular brakes are released in the endothelium, which in turn potentiate inflammation and vascular leakage. The ligands of Tie2, Angiopoietin-1 and Angiopoietin-2, regulate its activation status. Genetic and molecular studies spanning thousands of humans link Tie2 and imbalance of the Angiopoietins to major adverse clinical events arising from bacterial sepsis, other severe infections, and even acute sterile inflammation.

Summary: The Tie2 signaling axis may constitute a molecular switch in systemic inflammation that can be measured and manipulated to target the host vascular response therapeutically.

Figure 1. Tie2 signaling is finely tuned

Tie2 expression is heavily enriched in the endothelium. Its 2^nd immunoglobulin (Ig) domain ligates Angpts. Angpt-1 or -2 bind Tie2 via a C-terminal fibrinogen domain, and quarternary structural differences driven by the N-terminal superclustering (SCD) or coiled-coil (CCD) domains may account for the distinct actions of Angpt-1 as agonist vs. Angpt-2 as antagonist on Tie2. Angpt-1 is more highly oligomerized than Angpt-2 in vivo, and clustering of Tie2 monomers may be important for phosphorylation in its kinase domain. Tie1 is an orphan receptor in the endothelium that optimizes Tie2 signaling during inflammation. VE-PTP is a transmembrane tyrosine phosphatase that inhibits Tie2 signaling. Other abbreviations: EGF = epidermal growth factor repeat; FNIII = type 3 fibronectin domain. Adapted from (20).

Figure 2. Tie2 signaling prevents vascular leakage

Activated Tie2 migrates to cell junctions, remodels the cytoskeleton, and augments junctional accumulation of VE-cadherin. Compartmentalized intracellular signaling at intercellular junction may be important. Tie2 signals a complex of NADPH oxidase, its regulatory subunit p47phox, and the small GTPase Rac1. Rac1 is stabilized in its active GTP-bound form by IQGAP1. Rac1 itself signals the reorganization of the actin cytoskeleton toward a spread morphology, and by acting via the regulatory protein p190RhoGAP, inhibits the GTPase RhoA. Interaction of cortical actin via catenins (not depicted for ease of illustration) stabilizes VE-cadherin at the junction. VE-cadherin is essential for effective barrier formation in several microvascular beds.

Figure 3. Effects of Tie2 signaling in quiescence vs. vascular inflammation

During quiescence, Tie2 is highly phosphorylated and actively maintains homeostasis. One example of active maintenance of homeostasis is the inhibition of inflammatory transcription factor NFκB via the signaling protein ABIN2. During inflammatory stress, several changes collaborate to switch off Tie2 signaling: reduced Tie2 expression, reduced surface Tie2, reduced surface Tie1 by proteolysis, reduced extracellular Angpt-1, and increased extracellular Angpt-2 that itself arises from at least two distinct mechanisms—rapid release of pre-formed Angpt-2 protein from Weibel-Palade bodies and de novo biosynthesis as dephosphorylated Tie2 is no longer able to repress Foxo1. Induction of Angpt-2 potentiates vascular inflammation and exacerbates vascular leakage