Matrix Metalloproteinase 1 Causes Vasoconstriction and Enhances Vessel Reactivity to Angiotensin II via Protease-Activated Receptor 1

• Published in: Reproductive sciences (Thousand Oaks, Calif.) Vol. 23; no. 4; pp. 542 - 548
• Main Authors: Nugent, William H., Mishra, Nikita, Strauss, Jerome F., Walsh, Scott W.
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.04.2016; Springer International Publishing
• Subjects: Adult; Angiotensin II - pharmacology; Dose-Response Relationship, Drug; Drug Synergism; Embryology; Female; Humans; Matrix Metalloproteinase 1 - pharmacology; Medicine & Public Health; Obstetrics/Perinatology/Midwifery; Omentum - blood supply; Omentum - drug effects; Omentum - metabolism; Organ Culture Techniques; Original; Original Article; Pre-Eclampsia - metabolism; Pre-Eclampsia - pathology; Pregnancy; Pyrroles - pharmacology; Quinazolines - pharmacology; Receptor, PAR-1 - antagonists & inhibitors; Receptor, PAR-1 - metabolism; Reproductive Medicine; Vasoconstriction - drug effects; Vasoconstriction - physiology; Young Adult; vasoconstriction; protease-activated receptor 1; preeclampsia; hypertension; matrix metalloproteinase 1
• ISSN: 1933-7191; 1933-7205
• DOI: 10.1177/1933719115607998

Matrix metalloproteinase 1 (MMP-1) is an activator of protease-activated receptor 1 (PAR-1), which is known to mediate the release of endothelin 1 (ET-1) in endothelial cells and activate the RhoA kinase (ROCK) pathway. Recently, we reported increased serum and vascular MMP-1 in women with preeclampsia and hypothesized that the action of MMP-1 on PAR-1 might have vasoconstrictive effects. Resistance-sized omental arteries obtained from normal pregnant women were mounted on a myograph system and perfused with MMP-1 in a dose range of 0.025 to 25 ng/mL or with angiotensin II (Ang II) in a dose range of 0.001 to 10 µmol/L in the presence of intraluminal MMP-1 (2.5 ng/mL) perfusion. Angiotensin II dose response was also performed with omental arteries from women with preeclampsia. Matrix metalloproteinase 1 caused dose-dependent vasoconstriction in endothelium-intact, but not in endothelium-denuded, vessels from normal pregnant women, which was blocked by inhibitors of PAR-1 and ET-1 type A receptor blocker. Intraluminal perfusion with a constant amount of MMP-1 enhanced vessel reactivity to Ang II, which was blocked by inhibitors of PAR-1, ROCK, and ET-1. Enhanced vascular reactivity to Ang II was observed in endothelium-intact, but not in endothelium-denuded, arteries of women with preeclampsia. Inhibitors of PAR-1, ROCK, and ET-1 blocked enhanced vascular reactivity to Ang II in endothelium-intact preeclamptic arteries. These data demonstrate that MMP-1 has potent vasoconstrictor effects and the ability to enhance vascular reactivity to vasoconstrictor hormones, which are mediated by an endothelial PAR-1, ROCK, and ET-1 pathway. Increased circulating levels of MMP-1 and its increased expression in systemic vessels of women with preeclampsia may contribute to the development of maternal hypertension.