Methylation-reprogrammed CHRM3 results in vascular dysfunction in the human umbilical vein following IVF-ET

2021 ◽  
Author(s):  
Yajun Shi ◽  
Jingliu Liu ◽  
Dan Zhu ◽  
Likui Lu ◽  
Mengshu Zhang ◽  
...  
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Umbilical Vein ◽  
Plasma Lipid ◽  
Normal Pregnancy ◽  
Receptor Subtype ◽  
Functional Studies ◽  
Long Run ◽  
Mlc20 Phosphorylation ◽  
Ivf Et

Abstract Assisted reproductive technology (ART) has been used globally among infertile couples. However, many epidemiological investigations have indicated that ART is associated with a range of long-term adverse health outcomes in offspring, including cardiovascular disease, obesity and increased plasma lipid levels. Until now, direct evidence has been limited regarding the pathological changes in vascular function in fetuses with ART. In this study, human umbilical cords were collected from healthy normal pregnancies and IVF-ET pregnancies. Vascular functional studies involving acetylcholine (ACh), antagonists of its specific receptors, and L-type calcium channel/PKC-MLC20 phosphorylation pathway specific inhibitors were conducted. Quantitative real-time PCR, Western blotting and methylation analyses were performed on umbilical vein samples. We found that the umbilical vein constriction induced by ACh in the IVF-ET group was significantly attenuated compared with that in the healthy normal pregnancy group, which was not only associated with the hypermethylation of ACh muscarinic receptor subtype 3 (CHRM3) and decreased expression of CHRM3, PKCβ and CaV1.2, but was also related to the reduced phosphorylation of MLC20. The present study revealed that the hypermethylation of CHRM3, leading to a reduction in CHRM3 expression and downregulation of the CaV1.2/PKC-MLC20 phosphorylation pathway, was responsible for the decreased sensitivity to ACh observed in the umbilical vein under IVF-ET conditions. The hypermethylation of CHRM3 caused by IVF-ET might play an important role in altered vasoconstriction and impact cardiovascular systems in the long run.

scholarly journals Uteroplacental Circulation in Normal Pregnancy and Preeclampsia: Functional Adaptation and Maladaptation

2021 ◽  
Vol 22 (16) ◽  
pp. 8622
Author(s):  
Xiangqun Hu ◽  
Lubo Zhang
Keyword(s):  
Blood Flow ◽  
Hormonal Regulation ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Well Being ◽  
Normal Pregnancy ◽  
Functional Adaptation ◽  
Vasoactive Factors ◽  
Uteroplacental Blood Flow ◽  
Underlying Mechanisms

Uteroplacental blood flow increases as pregnancy advances. Adequate supply of nutrients and oxygen carried by uteroplacental blood flow is essential for the well-being of the mother and growth/development of the fetus. The uteroplacental hemodynamic change is accomplished primarily through uterine vascular adaptation, involving hormonal regulation of myogenic tone, vasoreactivity, release of vasoactive factors and others, in addition to the remodeling of spiral arteries. In preeclampsia, hormonal and angiogenic imbalance, proinflammatory cytokines and autoantibodies cause dysfunction of both endothelium and vascular smooth muscle cells of the uteroplacental vasculature. Consequently, the vascular dysfunction leads to increased vascular resistance and reduced blood flow in the uteroplacental circulation. In this article, the (mal)adaptation of uteroplacental vascular function in normal pregnancy and preeclampsia and underlying mechanisms are reviewed.

scholarly journals Residual vascular dysfunction in women with a history of preeclampsia

2018 ◽  
Vol 315 (6) ◽  
pp. R1062-R1071 ◽  
Author(s):  
Anna E. Stanhewicz
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Normal Pregnancy ◽  
The United States ◽  
Hypertensive Disorder ◽  
Vascular Endothelial ◽  
Cvd Risk ◽  
History Of ◽  
Hypertensive Disorder Of Pregnancy ◽  
Underlying Mechanisms

Preeclampsia is a hypertensive disorder of pregnancy characterized by new-onset hypertension, proteinuria, and edema occurring after 20 wk of gestation, with a prevalence of ~7–10% of pregnancies in the United States and ~8 million pregnancies worldwide. Despite the postpartum remission of preeclamptic symptoms, women who have had preeclampsia are two to four times more likely to develop cardiovascular disease (CVD) and are significantly more likely to die of CVD compared with women with a history of normal pregnancy. Although the relation between history of preeclampsia and elevated CVD risk is well documented, the mechanism(s) underlying this association remains unclear. One hypothesis explaining this association is that the initial vascular damage and dysfunction sustained during the preeclamptic pregnancy persist chronically. Indeed, even in the absence of, or in advance of, overt CVD women who have had preeclampsia have compromised vascular endothelial function. Emerging mechanistic studies in these women have provided some insight into the underlying mechanisms of this persistent vascular dysfunction and have begun to identify potential therapeutic targets for the prevention or mitigation of CVD progression in this vulnerable population. This review summarizes the existing literature examining vascular function and dysfunction in women with a history of preeclampsia and highlights future directions for mechanistic investigations and development of novel intervention strategies aimed at halting or slowing the progression of CVD in these women.

scholarly journals Gestational Diabetes Mellitus Treatment Schemes Modify Maternal Plasma Cholesterol Levels Dependent to Women´s Weight: Possible Impact on Feto-Placental Vascular Function

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 506 ◽  
Author(s):  
Susana Contreras-Duarte ◽  
Lorena Carvajal ◽  
María Jesús Garchitorena ◽  
Mario Subiabre ◽  
Bárbara Fuenzalida ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Gestational Diabetes ◽  
Gestational Diabetes Mellitus ◽  
Vascular Function ◽  
Plasma Cholesterol ◽  
Umbilical Vein ◽  
Maternal Plasma ◽  
Maternal Weight ◽  
Cholesterol Levels ◽  
The Impact

Gestational diabetes mellitus (GDM) associates with fetal endothelial dysfunction (ED), which occurs independently of adequate glycemic control. Scarce information exists about the impact of different GDM therapeutic schemes on maternal dyslipidemia and obesity and their contribution to the development of fetal-ED. The aim of this study was to evaluate the effect of GDM-treatments on lipid levels in nonobese (N) and obese (O) pregnant women and the effect of maternal cholesterol levels in GDM-associated ED in the umbilical vein (UV). O-GDM women treated with diet showed decreased total cholesterol (TC) and low-density lipoproteins (LDL) levels with respect to N-GDM ones. Moreover, O-GDM women treated with diet in addition to insulin showed higher TC and LDL levels than N-GDM women. The maximum relaxation to calcitonin gene-related peptide of the UV rings was lower in the N-GDM group compared to the N one, and increased maternal levels of TC were associated with even lower dilation in the N-GDM group. We conclude that GDM-treatments modulate the TC and LDL levels depending on maternal weight. Additionally, increased TC levels worsen the GDM-associated ED of UV rings. This study suggests that it could be relevant to consider a specific GDM-treatment according to weight in order to prevent fetal-ED, as well as to consider the possible effects of maternal lipids during pregnancy.

scholarly journals Age-Related Macular Degeneration: Role of Oxidative Stress and Blood Vessels

2021 ◽  
Vol 22 (3) ◽  
pp. 1296
Author(s):  
Yue Ruan ◽  
Subao Jiang ◽  
Adrian Gericke
Keyword(s):  
Oxidative Stress ◽  
Macular Degeneration ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Therapeutic Strategies ◽  
Vision Impairment ◽  
Age Related Macular Degeneration ◽  
Oxygen Species ◽  
Age Related

Age-related macular degeneration (AMD) is a common irreversible ocular disease characterized by vision impairment among older people. Many risk factors are related to AMD and interact with each other in its pathogenesis. Notably, oxidative stress and choroidal vascular dysfunction were suggested to be critically involved in AMD pathogenesis. In this review, we give an overview on the factors contributing to the pathophysiology of this multifactorial disease and discuss the role of reactive oxygen species and vascular function in more detail. Moreover, we give an overview on therapeutic strategies for patients suffering from AMD.

scholarly journals Programming of growth, insulin resistance and vascular dysfunction in offspring of late gestation diabetic rats

2009 ◽  
Vol 117 (3) ◽  
pp. 129-138 ◽  
Author(s):  
Emily M. Segar ◽  
Andrew W. Norris ◽  
Jian-Rong Yao ◽  
Shanming Hu ◽  
Stacia L. Koppenhafer ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Vascular Function ◽  
Vascular Dysfunction ◽  
Diabetic Rats ◽  
Late Gestation ◽  
Group Differences ◽  
Pregnant Rats ◽  
Increased Risk ◽  
Specific Insulin ◽  
Diabetic Mothers

ODM (offspring of diabetic mothers) have an increased risk of developing metabolic and cardiovascular dysfunction; however, few studies have focused on the susceptibility to disease in offspring of mothers developing diabetes during pregnancy. We developed an animal model of late gestation diabetic pregnancy and characterized metabolic and vascular function in the offspring. Diabetes was induced by streptozotocin (50 mg/kg of body weight, intraperitoneally) in pregnant rats on gestational day 13 and was partially controlled by twice-daily injections of insulin. At 2 months of age, ODM had slightly better glucose tolerance than controls (P<0.05); however, by 6 months of age this trend had reversed. A euglycaemic–hyperinsulinamic clamp revealed insulin resistance in male ODM (P<0.05). In 6–8-month-old female ODM, aortas had significantly enhanced contractility in response to KCl, ET-1 (endothelin-1) and NA (noradrenaline). No differences in responses to ET-1 and NA were apparent with co-administration of L-NNA (NG-nitro-L-arginine). Relaxation in response to ACh (acetylcholine), but not SNP (sodium nitroprusside), was significantly impaired in female ODM. In contrast, males had no between-group differences in response to vasoconstrictors, whereas relaxation to SNP and ACh was greater in ODM compared with control animals. Thus the development of diabetes during pregnancy programmes gender-specific insulin resistance and vascular dysfunction in adult offspring.

scholarly journals Soluble fms-Like Tyrosine Kinase 1 Is Increased in Preeclampsia But Not in Normotensive Pregnancies with Small-for-Gestational-Age Neonates: Relationship to Circulating Placental Growth Factor

2005 ◽  
Vol 90 (8) ◽  
pp. 4895-4903 ◽  
Author(s):  
Eiji Shibata ◽  
Augustine Rajakumar ◽  
Robert W. Powers ◽  
Robert W. Larkin ◽  
Carol Gilmour ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Gestational Age ◽  
Small For Gestational Age ◽  
Vascular Dysfunction ◽  
Normal Pregnancy ◽  
Maternal Serum ◽  
Placental Growth Factor ◽  
Gestational Age At Delivery ◽  
Placental Protein

Context: An excess of the soluble receptor, fms-like tyrosine kinase 1 (sFlt-1) may contribute to maternal vascular dysfunction in women with preeclampsia by binding and thereby reducing concentrations of free vascular endothelial growth factor and placental growth factor (PlGF) in the circulation. The putative stimulus for increased sFlt-1 during preeclampsia, placental hypoxia due to poor perfusion, is common to both preeclampsia and idiopathic intrauterine growth restriction. However, the latter condition occurs without maternal vascular disease. Objective: We asked whether, as with preeclampsia, sFlt-1 is increased and free PlGF is decreased in villous placenta and maternal serum of normotensive women with small-for-gestational-age (SGA) neonates. Study Design: This was a case-control study using banked samples. Groups of women with SGA neonates (birth weight centile &lt; 10th) and women with preeclampsia were matched to separate sets of normal pregnancy controls based on gestational age at blood sampling (serum) or gestational age at delivery (placenta). Results: sFlt-1 levels were higher in preeclamptics than controls (serum, P &lt; 0.0001; placental protein, P = 0.03; placental mRNA, P = 0.007) but not increased in SGA pregnancies. PlGF was lower in both preeclampsia (serum, P &lt; 0.0001; placental protein, P = 0.05) and SGA (serum, P = 0.0008; placental protein, P = 0.03) compared with their controls. PlGF in preeclampsia and SGA groups did not differ. Conclusions: These data are consistent with a role for sFlt-1 in the maternal manifestations of preeclampsia. In contrast to preeclampsia, sFlt-1 does not appear to contribute substantially to decreased circulating free PlGF in SGA pregnancies in the absence of a maternal syndrome.

scholarly journals Separation of important new platelet glycoproteins (GPIa, GPIc, GPIc*, GPIIa and GMP-140) by f.p.l.c. Characterization by monoclonal antibodies and gas-phase sequencing

1991 ◽  
Vol 279 (2) ◽  
pp. 419-425 ◽  
Author(s):  
B Catimel ◽  
S Parmentier ◽  
L L K Leung ◽  
J L McGregor
Keyword(s):  
Gas Phase ◽  
Polyclonal Antibodies ◽  
Umbilical Vein ◽  
Blood Platelets ◽  
Cdna Libraries ◽  
Membrane Glycoproteins ◽  
Terminal Sequence ◽  
Cdna Sequences ◽  
Functional Studies ◽  
Vinylidene Difluoride

A large number of membrane glycoproteins (around 40) are present on the surface of human blood platelets. Some of these glycoproteins are expressed in relatively small amounts, and their functions, as well as their structure, remain to be elucidated. The aim of the present study was to separate rapidly, under non-denaturing conditions, and characterize minor glycoproteins such as Very Late Antigens (VLA) (GPIa, GPIc, GPIc* and GPIIa) and GMP-140 (also known as PADGEM). VLAs and GMP-140 are respectively members of the integrin and selectin families. Platelet membrane glycoproteins were separated by wheat-germ agglutinin lectin affinity and Mono Q anion-exchange f.p.l.c. Peaks bearing isolated glycoproteins were electrophoresed on one- or two-dimensional SDS/polyacrylamide gels, Western blotted on to Immobilon poly(vinylidene difluoride) membranes and gas-phase-sequenced. The identity of isolated glycoproteins was also obtained by the use of monoclonal or polyclonal antibodies and tryptic peptide maps. Five minor [GPIa, GPIc, GPIc*, GPIIa and GMP 140 (PADGEM)], as well as a major (GPIIIb) glycoprotein, were eluted at low salt concentrations. GPIIb-IIIa and GPIb were eluted at high salt concentrations. The N-terminal sequence of platelet GPIa was identical with that obtained by Takada & Hemler [(1989) J. Cell Biol. 109, 397-407]. However, the N-terminal sequence of platelet GPIc + Ic* and GPIIa were found to differ from those deduced from cDNA sequences isolated from human placenta or umbilical-vein endothelial-cell cDNA libraries. The combined use of f.p.l.c. and gas-phase sequencing techniques provides a very powerful tool to separate and characterize rapidly platelet or other cellular proteins for structural, immunological and functional studies.

scholarly journals Vascular function and arginine and dimethylarginines in gentamicin-induced renal failure: a possible effect of heme oxygenase 1 inducer hemin

2017 ◽  
Vol 95 (12) ◽  
pp. 1406-1413 ◽  
Author(s):  
Esra Aycan-Ustyol ◽  
Merve Kabasakal ◽  
Seldag Bekpinar ◽  
F. Ilkay Alp-Yıldırım ◽  
Ozge Tepe ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Heme Oxygenase ◽  
Vascular Function ◽  
Asymmetric Dimethylarginine ◽  
Vascular Dysfunction ◽  
Cardiovascular Complication ◽  
Heme Oxygenase 1 ◽  
Antioxidant Enzyme Activities ◽  
Symmetric Dimethylarginine ◽  
Inflammatory Changes

Increased oxidative stress and disturbance in nitric oxide bioavailability lead to endothelial dysfunction and cardiovascular complication in renal disease. Gentamicin (GM), a commonly used antibiotic, exhibits a toxic effect on renal proximal tubules. Prevention of its nephrotoxicity is important. Therefore, we investigated whether heme oxygenase 1 HO-1) induction influenced kidney and vascular function in GM-administered rats. GM (100 mg·kg–1·day–1; i.p.) was given to rats alone or together with hemin (20 mg·kg–1 on alternate days; i.p.) for 14 days. Plasma and kidney l-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) as well as kidney 4-hydroxynonenal (HNE) levels and myeloperoxidase (MPO) activity were measured. Histopathological examinations of kidney and relaxation and contraction responses of aorta were also examined. GM increased serum SDMA, urea nitrogen (BUN), and creatinine levels and caused histopathological alterations in the kidney. GM elevated HO-1 protein and mRNA expressions, 4-HNE level, and MPO activity and decreased antioxidant enzyme activities and l-arginine levels in the kidney. Decreased relaxation and contraction were detected in the aorta. Hemin restored renal oxidative stress and inflammatory changes together with vascular dysfunction, but did not affect SDMA, BUN, or creatinine levels. We conclude that HO-1 induction may be effective in improving renal oxidative stress, inflammation, and vascular dysfunction mediated by GM.

scholarly journals DCE-MRI for Detection of Acute Myeloid Leukemia Derived Bone Marrow Vascular Dysfunction

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Ana Da Silva Gomes ◽  
Bernard Siow ◽  
Diana Passaro ◽  
Dominique Bonnet
Keyword(s):  
Bone Marrow ◽  
Vascular Permeability ◽  
Vascular Function ◽  
Myeloid Leukemia ◽  
Disease Burden ◽  
Vascular Dysfunction ◽  
Vascular Density ◽  
Dce Mri ◽  
Vascular Phenotype ◽  
Acute Myeloid

Acute Myeloid Leukemia (AML) is the most common acute leukemia in adults. While the clinical presentation is quite uniform, it is a highly heterogeneous disease at the genetic level. Using intravital two-photon microscopy in AML xenograft models, we have previously showed that AML patient-derived samples induced a common pathologic bone marrow (BM) vascular phenotype. To understand the translational potential of our findings we have optimized dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) for the assessment of BM vascular dysfunction. We quantified non-model based parameters from DCE-MRI scans: Contrast Enhancement (CE); Wash-in Rate (WiR); and Wash-out Rate (WoR). CE reflects tissue vascular density and is a measurement of the proportion of fully functional vessels per pixel area, WIR reflects blood flow and tissue perfusion, and WoR reflects vascular permeability and tissue clearance capacity. We first measured DCE parameters in control mice. We observed no gender-related differences in BM DCE parameters, while we found significant age-related changes. As mice age, BM vascular density decreases together with increased vascular permeability and reduced tissue clearance capacity. When compared to age- matched controls, mice injected with AML cell lines showed decreased vascular density, decreased blood inflow, increased vascular permeability and reduced tissue clearance capacity. There was a progressive decline in BM vascular function as the disease burden increased, particularly in WiR and WoR parameters, with even low levels of leukemia significantly altering BM vascular function. When analyzing mice injected with AML patient samples, changes in BM vascular function were more dependent on the AML sample than on the engraftment. Low disease burden did not significantly change DCE vascular parameters. At high disease burden, patient-derived xenografts show different degrees of vascular disruption, spanning from global altered DCE parameters to milder phenotypes. Upon AraC treatment, altered vascular parameters remained unchanged in most of the cases, suggesting inability to fully rescue BM vascular function. In conclusion, we showed that DCE-MRI is able to detect consistent changes associated with BM vasculature induced by aging and leukemia. Despite the heterogeneous nature of the disease, our method captures different degrees of vascular alterations, with WIR having the highest diagnostic potential. Our results further suggest that the detection of a pathologic vascular phenotype in the BM of AML patients could be of use in the clinical scenario. Disclosures No relevant conflicts of interest to declare.

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