Microvascular injury due to hypoxia and dysregulation of angiogenic factors such as VEGF is a very early pathogenic event in systemic sclerosis (SSc).
The angiopoietin/Tie2 system is a key regulator of angiogenesis. Tie2 is an endothelial cell receptor tyrosine kinase with Ang-1/2 as main ligands. The stable expression of membrane bound Tie2 and Ang-1 is responsible for vessel stability. Ang-2, inducible by VEGF, hypoxia and pro-inflammatory stimuli, antagonizes the Ang-1/Tie2 pathway, mainly in an autocrine manner. The Ang1/-2 ratio determines the functional status of the local vasculature. Both ligands bind to Tie2 with similar affinity. Since the levels of Ang-1 exceed those of Ang-2, the systemic effects of Ang-2 are abolished under physiological conditions. An imbalance towards Ang-2 has vessel destabilizing effects. In contrast to membrane bound Tie2, little is known about soluble Tie2 which is shedded by proteolytic cleavage upon stimulation with e.g. VEGF and hypoxia. Mainly due competitive ligand binding without signal transduction it exerts anti-angiogenic effects. Soluble Tie2 is detectable in healthy individuals, and increased serum concentrations were reported in cardiovascular diseases, diabetic retinopathy, and lately SSc.
As the previous studies exclusively analysed sera, we will now assess the role of the angiopoietin/Tie2 system in SSc-associated dermal microvasculopathy ex vivo and in four different animal models that mimic the dermal conditions of SSc.
Source: Saharinen P, Alitalo K. J Clin Invest. 2011 Jun;121(6):2157-9