Impairment of Protease-Activated Receptor 2-Induced Relaxation of Aortas of Aged Spontaneously Hypertensive Rat

Abstract

Hypertension is one of the most prevalent diseases worldwide and can cause harmful complications within the vascular system. Further research on vascular responsiveness to different ligands and diverse receptors in various arteries is required to understand the mechanisms underlying the development of these vascular complications. Here, we investigated the vasorelaxant effect of the protease-activated receptor 2 (PAR2) agonist 2-furoyl-LIGRLO-amide (2-Fly) and two commonest agents, namely endothelium-dependent dilator acetylcholine (ACh) and endothelium-independent dilator sodium nitroprusside (SNP), on the thoracic aorta isolated from aged spontaneously hypertensive rats (SHR) (age, 52 1 weeks). The effects of these agents were compared between aortas isolated from SHR and age-matched normotensive Wistar Kyoto (WKY) rats. Compared with the WKY group, in the SHR group, 2-Fly-induced relaxation was impaired, ACh-induced relaxation was slightly decreased at low concentrations, and SNP-induced relaxation was similar. In addition, 2-Fly-induced aortic relaxation was largely decreased by a PAR2 antagonist (FSLLRY), endothelial denudation, and a nitric oxide (NO) synthase inhibitor N G -nitro-L-arginine (L-NNA) but not by an Akt inhibitor. These results suggested that PAR2-induced relaxations of aortas of aged SHR was impaired, and this impaired aortic relaxation may be attributed to decreased NO bioavailability rather than altered NO sensitivity unrelated to the Akt activity.Key words aorta; endothelium; hypertension; protease-activated receptor 2 (PAR2); relaxation Vascular complications often occur systemically and arise in response to hypertension-associated pathologies, leading to increased mortality and morbidity rates in hypertensive patients worldwide.1) A growing body of evidence suggests that an abnormal vascular tone, for example, augmented contraction and/or restricted relaxation that was induced by various ligands in hypertensive patients and animal models. 2-4)However, completely understanding vascular tone regulation under pathophysiological conditions is highly complex because the action of one ligand on a receptor may evoke different responses among different vessel types. Thus, a better understanding of the association between hypertension and vascular tone, as modulated by receptor activation, will help identify new therapeutic targets for preventing and treating hypertension-associated vascular complications.Protease-activated receptor 2 (PAR2) is a member of the family of protease-activated receptors and is uniquely activated by proteolysis, PAR2 plays important roles in regulating diverse cellular processes during pathophysiological conditions such as atherosclerosis, diabetes, and hypertension. [5][6][7][8][9] In the vascular system, PAR2 activation can modulate the vascular tone. For example, PAR2 activation induced by the PAR2-activating peptide 2-furoyl-LIGRLO-amide (2-Fly) and endothelium-dependent relaxation induced by serine proteases occur by activating the endothelial nitric oxide syntha...