title: Matrix metalloproteinase enhances big-endothelin-1 constriction in mesenteric vessels of pregnant rats with reduced uterine blood flow.
abstract: Preeclampsia is a leading cause of maternal and fetal morbidity/mortality; however, the pathophysiological mechanisms are unclear. Vascular endothelial dysfunction in preeclampsia has been partially attributed to changes in endothelin-1 (ET-1). Several enzymes, including matrix metalloproteinases (MMPs; particularly MMP-2), cleave the inactive precursor big ET-1 (bET-1) to active ET-1. Notably, expression levels of MMP-2 have been shown to be on the increase in women who subsequently develop preeclampsia. We hypothesized that the increased MMP-2 expression leads to increased bET-1 conversion, thereby increasing vasoconstriction in preeclampsia. A reduced uteroplacental perfusion pressure (RUPP) model of preeclampsia in the rat was used to assess mesenteric artery vascular function. Responses to bET-1 (3-310 nmol/L) and ET-1 (1-200 nmol/L) were studied in the presence or absence of inhibitors of enzymes known to cleave bET-1. Vascular contractility in response to bET-1 was greater in RUPP than Sham (P<0.001), whereas neither responses to ET-1 nor maximal contractility to high potassium salt solution (123.70 mmol/L) were different. MMP inhibition with GM6001 (30 μmol/L) significantly decreased responses to bET-1 in RUPP (P<0.001) but not Sham-operated rats. Interestingly, combined treatment with GM6001 and L-NG-nitroarginine methyl ester (100 μmol/L) revealed a NO modulation of MMPs that was reduced in RUPP. In summary, we found increased vascular contractility to bET-1 in the RUPP model of preeclampsia that was likely attributable to upstream enzymatic pathways. These data are consistent with a greater contribution of MMP to cleavage of bET-1 to ET-1 ex vivo in RUPP, suggesting that this enzyme may be partially responsible for increased bET-1-induced contractility.
authors.affiliation: Department of Obstetrics/Gynecology, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Abdalvand
authors.forename: Jude S
authors.initials: JS
authors.lastname: Morton
authors.forename: Stephane L
authors.initials: SL
authors.lastname: Bourque
authors.forename: Anita L
authors.initials: AL
authors.lastname: Quon
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Davidge
mesh_terms: D000818:Animals; D004151:Dipeptides / Q000494:pharmacology; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D008643:Mesentery / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D011225:Pre-Eclampsia / Q000378:metabolism*; D011247:Pregnancy; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014599:Uterus / Q000098:blood supply* / Q000187:drug effects / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology*
chemical_list: D004151:Dipeptides; D019332:Endothelin-1; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D011480:Protease Inhibitors; D009569:Nitric Oxide; D020778:Matrix Metalloproteinase 2