Protease-activated receptors and EDHF: the icing on the cake?

The regulation of vascular smooth muscle cell tone by the vascular endothelium was initially described by Furchgott and Zawadzki, suggesting the existence of an endothelium-derived relaxing factor (EDRF) acting through cGMP, which was later identified as nitric oxide (NO) (see reference [1] for review). Since then, other actions of NO such as control of cell growth, blood cell–endothelial cell interactions, immunomodulatory functions, and antiaggregatory effects have been described [2]. In addition to NO and cyclooxygenase products, a third endotheliumderived principle, namely hyperpolarization of vascular smooth muscle cells in response to an endotheliumderived hyperpolarizing factor (EDHF), has been identified [3]. Production and bioactivity of endothelial factors are disturbed in cardiovascular diseases, and endotheliumdependent dilator mechanisms are counteracted by vasoconstrictory prostanoids that contribute to abnormal vascular function [4]. In this issue of Cardiovascular Research, Kawabata et al. report that activating peptides of the protease-activated receptor 2 (PAR2), namely trypsin and SLIGRL, cause endothelium-dependent relaxation by activating NO and EDHF pathways in rat mesenteric arteries in vitro. The authors show that gap junctions, but not epoxyeicosatrienoic acids, hydrogen peroxide, or K are involved in the release of EDHF in response to activation of PAR2. Moreover, vascular contractions due to an activating peptide of the protease-activated receptor 1 (TFLLR) were observed after inhibition of EDHF and NO or after endothelium removal.