Department of Obstetrics, Gynecology and Reproductive Sciences, University of Vermont, Burlington, Vermont 05405, USA.
Am J Physiol Heart Circ Physiol. 2011 Oct;301(4):H1266-75. doi: 10.1152/ajpheart.00519.2011. Epub 2011 Aug 19.
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.
最近的研究结果表明，内皮型一氧化氮合酶（NO）在妊娠期间子宫动脉外圆周重塑中起着关键作用。尽管其潜在机制尚不清楚，但它们可能涉及基质金属蛋白酶（MMPs）。本研究的目的是研究 NO 抑制、扩张性重塑和 MMP 表达之间的联系在子宫血管壁内。从妊娠第 10 天开始，成年雌性大鼠接受 N(G)-硝基-L-精氨酸甲酯 [L-NAME（LPLN）] 治疗，直到妊娠第 20 天死亡，并与年龄匹配的对照组（晚期妊娠（LP））进行比较。LPLN 大鼠的平均动脉压明显高于对照组。LPLN 胎儿和胎盘的重量明显低于对照组。收集主要子宫动脉（mUA）以确定尺寸特性（腔面积和壁厚度）、胶原和弹性蛋白含量以及内皮型一氧化氮合酶（eNOS）和 MMP 表达水平。圆周重塑减弱，表现为腔直径明显减小。与 LP 相比，LPLN mUA 中的 eNOS RNA 和蛋白质分别显著降低（>90%）。与 LP 相比，LPLN 大鼠的胶原和弹性蛋白含量分别显著增加（增加约 10%和 25%）（P <0.05）。通过免疫荧光法评估 MMP-2 和基质金属蛋白酶抑制剂-2 的组织抑制剂在 LPLN 中的表达分别降低了 60%和 50%。通过免疫印迹法评估的膜结合 MMP-1（MT1-MMP）在 LPLN 中显著降低。这些数据表明 MMPs 对妊娠子宫血管重塑有新的贡献，并证实了 NO 信号与妊娠期间子宫循环重塑之间的联系，通过改变 MMP、TIMP-2 和 MT1-MMP 的表达和活性。
