Figure 1.

Major EDCF-mediated signalling pathways in hypertension and diabetes. When intracellular Ca²⁺ levels are increased via the activation of GPCR by, for example, ACh, ADP or Ca²⁺ ionophore (A23187), AA is produced from membrane phospholipids by PLA₂. AA is metabolized to endoperoxides [PGG₂ and PGH₂] through activation of COXs (COX-1 and COX-2). PGH₂ is further metabolized into PGD₂, PGE₂, PGF₂α, PGI₂ and TxA₂ by specific synthases including PGDS, PGES, PGFS, PGIS and TxS. All these prostanoids and endoperoxides can activate TP receptors in vascular SMC leading to contraction via multiple pathways. Although PGI₂ usually leads to vasodilatation through activation of the IP receptor/adenylate cyclase (AC)/cAMP pathway, PGI₂ responses are impaired in some conditions, including hypertension and diabetes. Instead of abnormalities in the IP receptor/AC/cAMP pathway, other prostanoids such as PGE₂, PGF₂α and TxA₂, and endoperoxides may be increased and then stimulate TP receptors. In hypertensive arteries, mainly PGI₂, TxA₂ and PGH₂ mediate EDCF responses (in red). In addition to these prostanoids, PGE₂ and PGF₂α can also behave as EDCF in arteries from diabetic subjects (in blue). PGD₂ another EDCF has less significant effects compared with other PGs. COX generates ROS. ROS are considered EDCFs themselves as well as enhancers/modulators of EDCF responses, since ROS (1) further activate endothelial and smooth muscle COX and (2) increase production of isoprostanes via AA, leading to TP receptor activation. COX activity is regulated and further enhanced by several amplifier/inducers in hypertension and diabetes. Details are described in the text.