Protease-activated receptors, cyclo-oxygenases and pro-angiogenic signalling in endothelial cells

COX (cyclo-oxygenase)-2 and members of the PAR (protease-activated receptor) family (PARs 1–4) are highly overexpressed in a number of angiogenesis-dependent pathologies, including advanced atherosclerosis and cancer. An appreciation of the potential role(s) of PARs and COX enzymes in physiological angiogenesis is, however, currently lacking. Exposure of human endothelial cells to serine proteases (e.g. thrombin) or to PAR-selective agonist peptides leads to a wide range of cellular responses, including enhanced expression of COX-2, and we have shown that this induction depends on activation of classic pro-inflammatory signalling elements [e.g. MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor κB)]. Our current studies suggest that COX-2-derived mediators are important autocrine regulators of PAR-stimulated angiogenesis. This mechanism could help us to explain how this novel family of receptors couple vascular inflammation with repair and angiogenesis in health and disease.