Evidence for Selective Effects of Chronic Hypertension on Cerebral Artery Vasodilatation to Protease-Activated Receptor-2 Activation

Abstract

Background and Purpose-Protease-activated receptor-2 (PAR-2) can be activated after proteolysis of the amino terminal of the receptor by trypsin or by synthetic peptides with a sequence corresponding to the endogenous tethered ligand exposed by trypsin (eg, SLIGRL-NH 2 ). PAR-2 mediates nitric oxide (NO)-dependent dilatation in cerebral arteries, but it is unknown whether PAR-2 function is altered in cardiovascular diseases. Since hypertension selectively impairs NO-mediated cerebral vasodilatation in response to acetylcholine and bradykinin, we sought to determine whether PAR-2-mediated vasodilatation is similarly adversely affected by this disease state. Methods-We studied basilar artery responses in Wistar-Kyoto rats (WKY) (normotensive) and spontaneously hypertensive rats (SHR) in vivo (cranial window preparation) and in vitro (isolated arterial rings). The vasodilator effects of acetylcholine, sodium nitroprusside, and activators of PAR-2 and protease-activated receptor-1 (PAR-1) were compared in WKY versus SHR. Immunohistochemical localization of PAR-2 was also assessed in the basilar artery. Results-Increases in basilar artery diameter in response to acetylcholine were 65% to 85% smaller in SHR versus WKY, whereas responses to sodium nitroprusside were not different. In contrast to acetylcholine, vasodilatation in vivo to SLIGRL-NH 2 was largely preserved in SHR, and SLIGRL-NH 2 was Ϸ3-fold more potent in causing vasorelaxation in SHR versus WKY in vitro. In both strains, responses to SLIGRL-NH 2 were abolished by N

Increased Expression of Protease-Activated Receptor-2 (PAR2) and PAR4 in Human Coronary Artery by Inflammatory Stimuli Unveils Endothelium-Dependent Relaxations to PAR2 and PAR4 Agonists

“…It is interesting to note that in hypertension, although most other endothelium-dependent vasodilator function is diminished 33 and although there is an increased potential for thrombosis, 34 PAR2-mediated vasodilatation is preserved. 35 Further evidence that endothelial PAR2 is anti-inflammatory, albeit indirect, comes from our earlier observation in porcine isolated coronary arteries. We found that proinflammatory enzymes, such as bacterial thermolysin, which disable PAR2 without causing receptor activation, trigger a novel translation-dependent mechanism for replenishment of the cell surface receptor, which is rapid and specific for PAR2 over PAR1.…”

Presence of functionally active protease‐activated receptors 1 and 2 in myenteric glia

“…The recent finding of a thrombin-generating system in the brain and the presence of PAR-1 in neurons and glia suggest that PAR-1 may have functions in addition to revascularization (Ubl et al 1998). PAR-2 activation has been related to release of proteinases in inflammatory and allergic conditions, vasodilatation of cerebral arteries, release of prostaglandins, and regulation of cytokine production in enterocytes (Wakita et al 1997;Sobey et al 1999). In the gastrointestinal tract, PAR-2 may be activated by trypsin or tryptase, presumably released by mast cells within the gut wall (Corvera et al 1999).…”

Mechanism of trypsin‐induced endothelium‐dependent vasorelaxation in the porcine coronary artery

“…Trypsin-induced endothelium-dependent relaxation T. Nakayama et al Sobey et al, 1999). An endothelium-independent direct contractile e ect on the rabbit aorta (Komuro et al, 1997) and the endothelium-dependent contraction in the human umbilical vein (Saifeddine et al, 1998) were also reported.…”

“…Trypsin has been reported to cause endothelium-dependent vasorelaxation in various types of blood vessels including the porcine coronary artery (Hamilton & Cocks, 2000;Hamilton et al, 1998;Hwa et al, 1996;Sobey et al, 1999). Hamilton & Cocks (2000) have suggested that both NO and EDHF involved in trypsin-induced relaxation in the porcine coronary artery.…”