title: Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition.
abstract: Recent findings indicate that endothelial nitric oxide (NO) plays a key role in uterine artery outward circumferential remodeling during pregnancy. Although the underlying mechanisms are not known, they likely involve matrix metalloproteinases (MMPs). The goal of this study was to examine the linkage among NO inhibition, expansive remodeling, and MMP expression within the uterine vascular wall. Adult female rats were treated with N(G)-nitro-L-arginine methyl ester [L-NAME (LPLN)] beginning on day 10 of pregnancy and until death at day 20 and compared with age-matched controls [late pregnant (LP)]. Mean arterial pressure of LPLN rats was significantly higher than controls. LPLN fetal and placental weights were significantly reduced compared with controls. Main uterine arteries (mUA) were collected to determine dimensional properties (lumen area and wall thickness), collagen and elastin content, and levels of endothelial nitric oxide synthase (eNOS) and MMP expression. Circumferential remodeling was attenuated, as evidenced by significantly smaller lumen diameters. eNOS RNA and protein were significantly (>90%) decreased in the LPLN mUA compared with LP. Collagen and elastin contents were significantly increased in LPLN rats by ∼10 and 25%, respectively, compared with LP (P < 0.05). Both MMP-2 and tissue inhibitors of metalloproteinase-2 as assessed by immunofluorescence were lower in the endothelium (reduction of 60%) and adventitia (reduction of 50%) of LPLN compared with LP mUA. Membrane bound MMP-1 (MT1-MMP) as assessed by immunoblot was significantly decreased in LPLN. These data suggest a novel contribution of MMPs to gestational uterine vascular remodeling and substantiate the linkage between NO signaling and gestational remodeling of the uterine circulation via altered MMP, TIMP-2, and MT1-MMP expression and activity.
authors.affiliation: Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont, Burlington, Vermont 05405, USA. sarah.hale@uvm.edu
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Hale
authors.forename: Lindsey
authors.initials: L
authors.lastname: Weger
authors.forename: Maurizio
authors.initials: M
authors.lastname: Mandala
authors.forename: George
authors.initials: G
authors.lastname: Osol
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015153:Blotting, Western; D003094:Collagen / Q000096:biosynthesis / Q000502:physiology*; D004549:Elastin / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D005333:Fetus / Q000502:physiology; D005455:Fluorescent Antibody Technique; D007150:Immunohistochemistry; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D011247:Pregnancy / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis / Q000302:isolation & purification; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000096:biosynthesis; D055988:Uterine Artery / Q000187:drug effects / Q000502:physiology*
chemical_list: D011480:Protease Inhibitors; D019716:Tissue Inhibitor of Metalloproteinase-2; D009569:Nitric Oxide; D012313:RNA; D003094:Collagen; D004549:Elastin; D052250:Nitric Oxide Synthase Type III; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020781:Matrix Metalloproteinase 1