title: Matrix Metalloproteinase 1 Causes Vasoconstriction and Enhances Vessel Reactivity to Angiotensin II via Protease-Activated Receptor 1.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Nugent
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, USA Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Nikita
authors.initials: N
authors.lastname: Mishra
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Strauss
authors.affiliation: Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, VA, USA Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA, USA Scott.Walsh@vcuhealth.org.
authors.forename: Scott W
authors.initials: SW
authors.lastname: Walsh
mesh_terms: D000328:Adult; D000804:Angiotensin II / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000494:pharmacology*; D009852:Omentum / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D009924:Organ Culture Techniques; D011225:Pre-Eclampsia / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*; D055815:Young Adult; D010975:Platelet Aggregation Inhibitors
chemical_list: C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines; D044463:Receptor, PAR-1; D000804:Angiotensin II; D020781:Matrix Metalloproteinase 1; D010975:Platelet Aggregation Inhibitors
keywords: hypertension; matrix metalloproteinase 1; preeclampsia; protease-activated receptor 1; vasoconstriction