Annexin A2-Mediated Plasminogen Activation in Endothelial Cells Contributes to the Proangiogenic Effect of Adenosine A2A Receptors

Abstract

Adenosine A2A receptor mediates the promotion of wound healing and revascularization of injured tissue, in healthy and animals with impaired wound healing, through a mechanism depending upon tissue plasminogen activator (tPA), a component of the fibrinolytic system. In order to evaluate the contribution of plasmin generation in the proangiogenic effect of adenosine A2A receptor activation, we determined the expression and secretion of t-PA, urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) and annexin A2 by human dermal microvascular endothelial cells stimulated by the selective agonist CGS-21680. The plasmin generation was assayed through an enzymatic assay and the proangiogenic effect was studied using an endothelial tube formation assay in Matrigel. Adenosine A2A receptor activation in endothelial cells diminished the release of PAI-1 and promoted the production of annexin A2, which acts as a cell membrane co-receptor for plasminogen and its activator tPA. Annexin A2 mediated the increased cell membrane-associated plasmin generation in adenosine A2A receptor agonist treated human dermal microvascular endothelial cells and is required for tube formation in an in vitro model of angiogenesis. These results suggest a novel mechanism by which adenosine A2A receptor activation promotes angiogenesis: increased endothelial expression of annexin A2, which, in turn, promotes fibrinolysis by binding tPA and plasminogen to the cell surface.

Integrated histopathology, spatial and single cell transcriptomics resolve cellular drivers of early and late alveolar damage in COVID-19

“…3D, Table S5). We also observed downregulation of ANXA2 (Annexin A2), which typically acts as a receptor for PLAT/ tPA to promote fibrinolysis (Valls et al , 2021), as well as downregulation of PROCR (protein C receptor) and THBD (thrombomodulin), which together are required for activation of protein C, and downstream inhibition of SERPINE1 /PAI-1 (Barranco-Medina et al , 2017) (Fig. 3C-D).…”

Dietary adenosine supplementation improves placental angiogenesis in IUGR piglets by up-regulating adenosine A2a receptor

“…As an endogenous purine nucleoside, adenosine exerts its biological effects by activating its 4 adenosine receptor subtypes, including adenosine A1 receptor (ADORA1); adenosine A2a receptor (ADORA2A); adenosine A2b receptor (ADORA2B) and adenosine A3 receptor (ADORA3) ( Salsoso et al., 2017 ). Previous studies have confirmed the promoting role of adenosine in biological and pathological angiogenesis ( Antonioli et al., 2021 ; Troncoso et al., 2020 ; Valls et al., 2021 ). Additionally, adenosine was reported to activate ADORA2A to potentiate angiogenesis by regulating the levels of angiogenesis factors including vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1α (HIF-1α) ( Escudero et al., 2013 ; Fernandez et al., 2012 ; Liu et al., 2017 ).…”

Collagen-I influences the post-translational regulation, binding partners and role of Annexin A2 in breast cancer progression

“…Having confirmed the interaction between Annexin A2 and fibronectin, we next examined its functional consequence. It is reported that when Annexin A2 becomes phosphorylated and translocated to the extracellular surface, it acts as an activation platform for plasmin, a protease known to directly degrade ECM proteins including fibronectin ( 27 , 66 , 67 ). We hypothesized that Annexin A2 could regulate the degradation of fibronectin, as a known interactor of both plasminogen and its activators ( 27 , 29 ), and a novel interactor of fibronectin.…”

“…It is reported that when Annexin A2 becomes phosphorylated and translocated to the extracellular surface, it acts as an activation platform for plasmin, a protease known to directly degrade ECM proteins including fibronectin ( 27 , 66 , 67 ). We hypothesized that Annexin A2 could regulate the degradation of fibronectin, as a known interactor of both plasminogen and its activators ( 27 , 29 ), and a novel interactor of fibronectin. To test our hypothesis, we assessed the direct effect of Annexin A2 expression on the degradation of fibronectin using a modified gelatin degradation assay ( 68 ) and high-throughput immunofluorescent imaging.…”