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.
Highlights
Adenosine is a ubiquitous nucleoside that participates actively in regulating different physiological processes involved in tissue repair and wound healing, inflammatory and immune responses, or formation of new blood vessels (Valls et al, 2009; Borea et al, 2018)
Since we have previously shown that adenosine A2A receptor activation promoted wound revascularization by promoting both angiogenesis and vasculogenesis (Montesinos and Valls, 2010), we investigated its effect on human dermal microvascular endothelial cells (HDMVEC)
We report here evidence for a novel mechanism by which adenosine receptors promote angiogenesis: stimulation of adenosine A2A receptors promotes the expression of annexin A2 on the surface of endothelial cells, which binds tissue plasminogen activator (tPA) to the surface of the cells, providing for localized activation of plasminogen to plasmin
Summary
Adenosine is a ubiquitous nucleoside that participates actively in regulating different physiological processes involved in tissue repair and wound healing, inflammatory and immune responses, or formation of new blood vessels (Valls et al, 2009; Borea et al, 2018). Plasminogen and its active form plasmin belong to an enzymatic system involved in intravascular and extravascular fibrinolysis, as well as in tissue repair and remodeling by regulating extracellular matrix degradation, cell migration, tissue formation, angiogenesis, and embryogenesis (Rubina et al, 2017; Plekhanova et al, 2019). The activity of this system is self-regulated by several factors such as tissue-type plasminogen activator (t-PA), urokinase-type plasminogen activator (u-PA) or the plasminogen activator principal inhibitor PAI-1 (Simone et al, 2015). Annexin A2 deficient mice present deficiencies in plasmin generation through a mechanism dependent on t-PA (Ling et al, 2004)
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