Endothelium-Dependent Contraction: The Non-Classical Action Of Endothelial Prostacyclin, Its Underlying Mechanisms, And Implications

Although commonly thought to produce prostacyclin (prostaglandin I-2; PGI(2)) that evokes vasodilatation and protects vessels from the development of diseases, the endothelial cyclooxygenase (COX)-mediated metabolism has also been found to release substance(s) called endothelium-derived contracting factor(s) (EDCF) that causes endothelium-dependent contraction and implicates in endothelial dysfunction of disease conditions. Various mechanisms have been proposed for the process; however, the major endothelial COX metabolite PGI(2), which has been classically considered to activate the I prostanoid receptor (IP) that mediates vasodilatation and opposes the effects of thromboxane (Tx) A(2) produced by COX in platelets, emerges as a major EDCF in health and disease conditions. Our recent studies from genetically altered mice further suggest that vasomotor reactions to PGI(2) are collectively modulated by IP, the vasoconstrictor Tx-prostanoid receptor (TP; the prototype receptor of TxA(2)) and E prostanoid receptor-3 (EP3; a vasoconstrictor receptor of PGE(2)) although with differences in potency and efficacy; a contraction to PGI(2) reflects activities of TP and/or EP3 outweighing that of the concurrently activated IP. Here, we discuss the history of endothelium-dependent contraction, evidences that support the above hypothesis, proposed mechanisms for the varied reactions to endothelial PGI(2) synthesis as well as the relation of its dilator activity to the effect of another NO-independent vasodilator mechanism, the endothelium-derived hyperpolarizing factor. Also, we address the possible pathological and therapeutic implications as well as questions remaining to be resolved or limitations of our above findings obtained from genetically altered mouse models.