This classification was proposed by Mulvany (86) and is further refined to include consideration of wall mass, which can increase (hypertrophy), decrease (hypotrophy), or remain unchanged (eutrophy). Various patterns of arterial remodeling are shown in FIGURE 1; see legend for additional detail and for consideration of how changes in crosssectional area, a two-dimensional quantity (e.g., m 2 ), relate to changes in wall mass, a three-dimensional quantity (e.g., m 3 ). Uterine Hemodynamics DuringPregnancy; Blood Flow Patterns and the Importance of Placentation Type Uterine vascular anatomyAn overview of comparative uterine vascular anatomy is presented in FIGURE 2, which describes and illustrates the uterine circulation in humans (FIGURE 2A), rodents (FIGURE 2B), and ungulates, such as sheep and pigs. Please see legend for additional detail.Uterine and placental blood flow during pregnancy Early (1953Early ( -1960 human studies by Assali et al (3, 4) and Metcalfe (78) utilizing the diffusion equilibrium principle (most often nitrous oxide, N 2 O) or electromagnetic flow probes placed directly on the uterine artery reported that total uteroplacental blood flow (UPBF) increases from a baseline value of 20-50 ml/min to 450-800 ml/min in singleton pregnancies, with values in excess of 1 l/min measured in twin pregnancy. Subsequent measurements of uterine artery blood flow with 133 Xe (106), placental metabolic clearance rate techniques (29) The clinical relevance of maternal uterine vascular adaptation during pregnancy is underscored by the fact that its aberrance is associated with several common gestational pathologies, including intrauterine growth restriction, gestational diabetes, and preeclampsia.In addition to the changes in vessel structure, uterine vascular reactivity is also altered during pregnancy, with the general pattern being one of reduced tone and enhanced vasodilation/blunted vasoconstriction (52,72,111,112,118). Space limitations preclude indepth consideration of the ionic and enzymatic mechanisms that underlie reactivity, but it is worth noting that, in vivo, uterine vascular resistance (and, therefore, blood flow) is ultimately determined by the combination of vessel size and reactivity.We also avoid examining the complex angiogenic mechanisms associated with implantation and placentation, other than to consider how hemochorial vs. epitheliochorial placentation influences uterine hemodynamics and vascular remodeling. Although the remodeling of spiral arteries by fetal trophoblast is considered, the main focus of this review is on upstream maternal uterine arteries and veins, since the processes involved in their remodeling have not been reviewed to date. Readers interested in endovascular trophoblast invasion and mechanisms underlying spiral artery remodeling are referred to several reviews on this subject (9, 31, 71, 101). Nomenclature Used to Describe Vascular RemodelingCircumferential remodeling is normally termed inward or outward to denote narrowing vs. widening of the vessel lumen. The ...

The objectives of this study were to determine whether placental growth factor (PlGF) exerts a vasodilatory effect on rat uterine vessels (arcuate arteries and veins) and to examine regional differences in reactivity by comparing these responses to those of comparably sized mesenteric vessels. We also sought to examine and compare its effects on human uterine and subcutaneous vessels. All vessels were studied in vitro, under pressurized (rat) or isometric wire-mounted (human) conditions, and exposed to a range of PlGF concentrations. Inhibitors of nitric oxide and prostaglandin synthesis were included in an effort to understand the causal mechanism(s). In rat uterine arteries, the effects of receptor inhibition and activation using selective ligands for VEGFR-1 (PlGF) vs. VEGFR-2 (VEGF-E) were determined, and real-time RT-PCR was performed to evaluate the effect of pregnancy on relative abundance of VEGFR-1 and VEGFR-2 message in the vascular wall. PlGF was a potent vasodilator of all vessels studied, with greatest sensitivity observed in rat uterine arteries. Pregnancy significantly augmented dilator sensitivity to PlGF, and this effect was associated with selective upregulation of VEGFR-1 message in the pregnant state. The contribution of nitric oxide was appreciable in rat and human uterine arteries, with lesser effects in rat uterine veins and mesenteric arteries, and with no observable effect in human subcutaneous vessels. Based on these results, we conclude that PlGF is a potent vasodilator of several vessel types in both humans and rats. Its potency and mechanism vary with physiological state and vessel location and are mediated solely by the VEGFR-1 receptor subtype. Gestational changes in the uterine circulation suggest that this factor may play a role in modulating uterine vascular remodeling and blood flow during the pregnant state.

Sufficient uteroplacental blood flow is essential for normal pregnancy outcome and is accomplished by the coordinated growth and remodelling of the entire maternal uterine vasculature. The main focus of this MiniReview is to provide information on upstream (pre-placental) maternal uterine vascular remodelling that facilitates gestational increases in uterine blood flow. Consideration of the three-dimensional pattern of remodelling (circumferential enlargement versus axial elongation), changes in vessel biomechanical properties, and underlying mechanisms [shear stress, nitric oxide, vascular endothelial growth factor (VEGF) ⁄ placental growth factor (PlGF), the renin-angiotensin system] and pathways (local versus systemic; venoarterial exchange) are provided using the rat as the principal animal model, although findings from other species are incorporated wherever possible to provide a comparative perspective. The process of maternal gestational uterine vascular remodelling involves a number of cellular processes and mechanisms, including trophoblast invasion, hyperplasia and hypertrophy, and changes in extracellular matrix composition. In addition, changes in cellular function, e.g. the secretory and contractile properties of smooth muscle and an up-regulation of endothelial vasodilatory influences may contribute to uteroplacental blood flow increases through changes in tone as well as in structure. Future studies aimed at better understanding the inter-relationship between changes in vessel structure (remodelling) and function (reactivity) would likely generate new mechanistic insights into the fascinating process of maternal gestational uterine vascular adaptation and provide a more physiological perspective of the underlying cellular processes involved in its regulation.

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SummaryThe transcription of ribosomal RNA genes (rDNA) is subject to epigenetic regulation, as it is abrogated by the methylation of CpG dinucleotides within their promoter region. Here, we investigated, through Sequenom platform, the age‐related methylation status of the CpG island falling into the rDNA promoter in 472 blood samples from 20‐ to 105‐year‐old humans and in different tissues (blood, heart, liver, kidney, and testis) of 15 rats 3–96 weeks old. In humans, we did not find a consistently significant correlation between CpG site methylation and chronological age. Furthermore, the methylation levels of one of the analyzed CpG sites were negatively associated with both cognitive performance and survival chance measured in a 9‐year follow‐up study. We consistently confirmed such result in a replication sample. In rats, the analysis of the homologous region in the tissues revealed the existence of increased methylation in old rats. rRNA expression data, in both humans and rats, were consistent with observed methylation patterns, with a lower expression of rRNA in highly methylated samples. As chronological and biological ages in rats of a given strain are likely to be much closer to each other than in humans, these results seem to provide the first evidence that epigenetic modifications of rDNA change over time according to the aging decline. Thus, the methylation profile of rDNA may represent a potential biomarker of aging.

Background/Aims: It was the aim of this study to test the hypothesis that hypertension and/or inhibition of nitric oxide (NO) synthases alters uterine vascular remodeling during pregnancy. Methods: Using a model of hypertension (NO synthase inhibition with L-NAME) in nonpregnant and pregnant rats, comparisons were made with age-matched controls, as well as with animals receiving hydralazine along with L-NAME to maintain normotension in the presence of NO synthase inhibition. Circumferential and axial remodeling of large (main uterine, MUA) and small (premyometrial radial) arteries were quantified and compared. Results:L-NAME treatment prevented expansive circumferential remodeling of the MUA; cotreatment with hydralazine was without effect. Circumferential remodeling of smaller premyometrial radial arteries was also significantly attenuated in hypertensive pregnant animals, while premyometrial radial arteries from rats receiving hydralazine with L-NAME were of intermediate diameter. Neither hypertension nor NO synthase inhibition had any effect on the substantial (200–300%) axial growth of MUA or premyometrial radial arteries. Conclusion: NO plays a major role in facilitating pregnancy-induced expansive remodeling in the uterine circulation, particularly in larger arteries. Some beneficial effects of hydralazine on expansive circumferential remodeling were noted in smaller radial vessels, and these may be linked to its prevention of systemic hypertension and/or to local effects on the arterial wall. Neither NO synthase inhibition nor hypertension had any effect on arterial longitudinal growth.

. Uterine artery myosin phosphatase isoform switching and increased sensitivity to SNP in a rat L-NAME model of hypertension of pregnancy. Am J Physiol Cell Physiol 294: C564-C571, 2008. First published December 19, 2007 doi:10.1152/ajpcell.00285.2007.-Dramatic and vascular bed-specific hemodynamic changes occur in pregnancy and hypertension of pregnancy (HtP). Because myosin phosphatase (MP) is the primary effector of smooth muscle relaxation and a key target of signaling pathways that regulate vascular tone, we hypothesized that MP expression would be altered in these conditions. The abundance of the targeting/regulatory subunit of MP (MYPT1) mRNA and protein was increased 1.7-to 2.0-fold specifically in the uterine arteries (UAs) of late-pregnant rats without isoform switching. In a model of HtP in which nitric oxide (NO) synthesis is blocked by the chronic administration of N -nitro-L-arginine methyl ester, MYPT1 was downregulated and switched to the splice variant isoform that codes for the COOH-terminal leucine zipper motif. This was associated with increased sensitivity of the main UA and its subbranches to the vasorelaxant effects of the NO donor drug sodium nitroprusside. This difference was abolished by pretreatment with the phosphatase inhibitor tautomycetin. The sensitivity of relaxation to the NO second messenger cGMP was also increased under calciumclamp conditions in permeabilized UAs, indicating heightened activation of MP. The changes in MP expression in HtP were largely prevented by treatment with the antihypertensive medicine hydralazine. We propose that MYPT1 isoform switching is an adaptive response to reduce vascular resistance and maintain uterine blood flow in the setting of hypertension-triggered inward remodeling of the UAs in hypertension of pregnancy. smooth muscle; gene expression; guanosine 3Ј,5Ј-cyclic monophosphate; contractility; signaling; N -nitro-L-arginine methyl ester; sodium nitroprusside A MULTITUDE OF CHANGES OCCUR in the circulation of mammals during normal pregnancy. One critical adaptation is the fall in the uterine vascular resistance that allows for the 15-to 20-fold increase in uterine blood flow needed to nourish the growing fetus. Approximately 5-10% of human pregnancies are complicated by hypertensive disorders of pregnancy leading to increased perinatal morbidity and mortality for the mother and fetus (12,22). These disorders include pregnancy-induced hypertension, chronic hypertension, preeclampsia, and eclampsia. A number of studies have suggested that the pregnancyrelated reduction in vascular resistance, particularly in the uterine vascular bed, is in part due to increased synthesis and activity of endothelium-derived vasodilators such as nitric oxide (NO) and prostacyclin (reviewed in Ref. 1). Similarly, it has been proposed that endothelial dysfunction, manifest as defective release/activity of the vasodilators, as well as increased release and activity of vasoconstrictors such as angiotensin II, thromboxane, and endothelin, may contribute to the elevated...

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