Angiopoietin 2 signal complexity in cardiovascular disease and cancer

Altered Ang1/Ang2 balance has been reported in various pathological conditions in association with inflammation and deregulated angiogenesis. In particular, increased Ang2 levels have been documented in human cancer and cardiovascular disease (CVD), including ischemic myocardial injury, heart failure and other cardiovascular complications secondary to diabetes, chronic renal damage and hypertension. Despite the obvious phenotypic differences, CVD and cancer share some common Ang2-dependent etiopathological mechanisms such as inflammation, epithelial (or endothelial) to mesenchymal transition, and adverse vascular network remodeling. Interestingly, both cancer and CVD are negatively affected by thyroid hormone dyshomeostasis.

The angiopoietin signal transduction system is a complex of vascular-specific kinase pathways that plays a crucial role in angiogenesis and maintenance of vascular homeostasis. Angiopoietin1 (Ang1) and 2 (Ang2), the ligand proteins of the pathway, belong to a family of glycoproteins that signal primarily through the transmembrane Tyrosine-kinase-2 receptor. Despite a considerable sequence homology, Ang1 and Ang2 manifest antagonistic effects in pathophysiological conditions. While Ang1 promotes the activation of survival pathways and the stabilization of the normal mature vessels, Ang2 can either favor vessel destabilization and leakage or promote abnormal EC proliferation in a context-dependent manner.