Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition

Abstract

Hale SA, Weger L, Mandala M, Osol G. Reduced NO signaling during pregnancy attenuates outward uterine artery remodeling by altering MMP expression and collagen and elastin deposition. Am J Physiol Heart Circ Physiol 301: H1266 -H1275, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00519.2011.-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 (Ͼ90%) decreased in the LPLN mUA compared with LP. Collagen and elastin contents were significantly increased in LPLN rats by ϳ10 and 25%, respectively, compared with LP (P Ͻ 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. matrix metalloproteinase; extracellular matrix; hypertension; pregnancy; nitric oxide DURING PREGNANCY, THE UTERINE vasculature undergoes significant expansive remodeling to accommodate the dramatic increase in uteroplacental blood flow that is requisite for normal pregnancy outcome. Studies from our and other laboratories (40,41,44,46,50,61) have established that nitric oxide (NO) is a key molecule involved in vascular remodeling during pregnancy and that expression of endothelial nitric oxide synthase (eNOS) is increased during pregnancy, leading to increased synthesis and release of NO from the endothelium.The importance of NO and NO signaling during pregnancy is underscored by the vascular and reproductive implications evident in mouse knockouts for endothelial NO synthase and in rats treated with the NO inhibitor N G -nitro-L-arginine methyl ester (L-NAME) during pregnancy (50, 64). Tre...

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