scholarly journals Pregnancy late in rodent life has detrimental effects on the heart

2018 ◽  
Vol 315 (3) ◽  
pp. H482-H491 ◽  
Author(s):  
Eunhee Chung ◽  
Kaylan M. Haizlip ◽  
Leslie A. Leinwand
Keyword(s):  
Contractile Function ◽  
Cardiac Response ◽  
Stressful Event ◽  
Vascular Endothelial ◽  
Pregnant Mice ◽  
Lower Fertility ◽  
Adverse Pregnancy ◽  
Endothelial Growth Factor ◽  
Fractional Shortening ◽  
Chamber Size

During pregnancy, the heart undergoes significant and numerous changes, including hypertrophy, that are usually described as physiological and reversible. Two aspects of the cardiac response to pregnancy are relatively understudied: advanced maternal age and multiple pregnancies (multiparity). Repeated breeder (RB) mice that have undergone five to seven consecutive pregnancies were euthanized 21 days after the weaning of their last pups and compared with age-matched primiparous, one-time pregnant (O1P) mice. The ages of the older mouse groups were similar (12 ± 1 mo). Pregnancy at a later age resulted in reduced fertility (40%); resorption was 29%, maternal mortality was 10%, and mortality of the pups was 17%. Contractile function as indicated by percent fractional shortening was significantly decreased in O1P and RB groups compared with the old nonpregnant control (ONP) group. There was no pathological induction of the fetal program of gene expression, with the exception of β-myosin heavy chain mRNA, which was induced in O1P compared with ONP mice ( P < 0.05) but not in RB mice. MicroRNA-208a was significantly increased in O1P compared with ONP mice ( P < 0.05) but significantly decreased in RB compared with ONP mice ( P < 0.05). mRNA of genes regulating angiogenesis (i.e., vascular endothelial growth factor-A) were significantly downregulated, whereas proinflammatory genes [i.e., interleukin-6, chemokine (C-C motif) ligand 2, and Cd36] were significantly upregulated in O1P ( P < 0.05) but not in RB mice. Overall, our results suggest that rather than multiparity, pregnancy in advanced age is a much more stressful event in both pregnant dams and fetuses, as evidenced by increased mortality, lower fertility, downregulation of angiogenesis, upregulation of inflammation, and cardiac dysfunction. NEW & NOTEWORTHY Pregnancy in older mice significantly decreases cardiac function, although repeated breeder mice demonstrated increased wall hypertrophy and dilated chamber size compared with one-time pregnant mice. Interestingly, many of the molecular changes were altered in one-time pregnant mice but not in repeated breeder mice, which may contribute to adverse pregnancy outcomes in a first pregnancy at a later age.

scholarly journals THE EFFECT OF RECOMBINANT VASCULAR ENDOTHELIAL GROWTH FACTOR 121 ON NITRIDE OXIDE LEVEL IN MICE (Mus musculus) MODEL OF PREECLAMPSIA

2017 ◽  
Vol 53 (3) ◽  
pp. 191
Author(s):  
Soetrisno Soetrisno ◽  
Isharyadi Isharyadi ◽  
Sri Sulistyowati
Keyword(s):  
Nitric Oxide ◽  
Mus Musculus ◽  
P Value ◽  
Vascular Endothelial ◽  
The Third ◽  
Minimum Value ◽  
Maximum Value ◽  
Pregnant Mice ◽  
Endothelial Growth Factor ◽  
K2 Group

Preeclampsia is a multifactorial syndrome in pregnancy whose cause is still unknown. Several proangiogenic and antiangiogenic mediators such as Vascular Endothelial Growth Factor (VEGF) and Nitrite Oxide (NO) play important roles in preventing preeclampsia. VEGF can increase NO level that lowers maternal blood pressure, improves endothelial function and reduces placental hypoxia in preeclampsia. Recombinant VEGF 121 is expected to be an option in the prevention and treatment of preeclampsia. This experimental study used mice (Mus musculus) as the model. The objective of this study was to observe the effect of recombinant VEGF 121 in increasing the level of nitric oxide in mice (Mus musculus) model of preeclampsia. This was an experimental analytical study with Randomized Control Trial (RCT) design. The study enrolled 27 pregnant mice (Mus musculus) which met the restriction criteria divided into 3 groups. The first group (K1) were 9 normal pregnant mice. The second group (K2) were 9 pregnant mice of preeclampsia model without treatment. The third group (K3) were 9 pregnant mice of preeclampsia model receiving recombinant VEGF 121 therapy. The independent variable was the administration of recombinant VEGF 121 and the dependent variable was the serum NO level. Statistical analysis was performed by using anova statistics. NO level in the first group (K1) was 1.746±0.347, with minimum value of 1.00 µM, and maximum value of 2.28 µM, CI (1.479-2.013).  NO level in second group (K2) was 1.167±0.380, with minimum value of 0.64 µM, and maximum value of 1.94 µM, CI (0.875-1.460). NO level in the third group (K3) was 2.164±0.556, with minimum value of 1.56 µM, and maximum value of 5.96 µM, CI (1.842-2.486). With anova statistical test, there were significant differences between K1 group and K2 group (p value=0.004<0.05), K1 group and K3 group (p value=0.000<0.05) as well as K2 group and K3 group (p value=0.029<0.05). In conclusion, Recombinant VEGF 121 increased the level of nitric oxide in mice (Mus musculus) model of preeclampsia significantly.

Decreased cardiac expression of vascular endothelial growth factor and redox imbalance in murine diabetic cardiomyopathy

2009 ◽  
Vol 297 (2) ◽  
pp. H829-H835 ◽  
Author(s):  
Bing Han ◽  
Reshma Baliga ◽  
Hong Huang ◽  
Peter J. Giannone ◽  
John Anthony Bauer
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Type 1 Diabetes ◽  
Growth Factor ◽  
Vascular Endothelial ◽  
Redox Imbalance ◽  
Endothelial Growth Factor ◽  
Vegf Isoforms ◽  
Fractional Shortening ◽  
Microvascular Rarefaction

Type 1 diabetes is associated with a unique form of cardiomyopathy that is present without atherosclerosis. Redox imbalance and/or changes in vascular endothelial growth factor (VEGF) expression have been associated with diabetes-related cardiomyopathy. However, the mechanisms of these changes and their interrelationships remain unclear. Using a murine type 1 diabetes model, we tested the hypothesis that alterations in cardiac performance are associated with decreased cardiac microvascular prevalence, as well as downregulation of VEGF isoforms. We also investigated oxidative stress as a contributor to regulate individual VEGF isoforms and microvascular rarefaction. Significant and rapid hyperglycemia was observed at 1 wk post-streptozotocin (STZ) and persisted throughout the 5-wk study. Left ventricular (LV) fractional shortening was reduced at week 1 and 5 post-STZ insult relative to age-matched controls. We also observed the early reduction in E/A ratio at 1 wk. Immunostaining for CD31 and digital image analysis demonstrated a 35% reduction in microvessels/myocardial area, indicative of rarefaction, which was highly correlated with fractional shortening. Furthermore, a significant increase in the prevalence of protein 3-nitrotyrosine was observed in the diabetic cardiac tissue, which was inversely associated with microvascular rarefaction. The expressions of three VEGF isoforms were significantly reduced to different extents. The reduction of VEGF164 was associated with GSSG accumulation. These data demonstrate that the mouse model of STZ-induced diabetes has hallmark features observed in humans with respect to nonischemic systolic and diastolic performance and microvascular rarefaction, which are associated with changes in VEGF isoform expression and redox imbalance in the myocardium.

Evidence of proteinuria, but no other characteristics of pre-eclampsia, in relaxin-deficient mice

2017 ◽  
Vol 29 (8) ◽  
pp. 1477 ◽  
Author(s):  
Kelly P. O'Sullivan ◽  
Sarah A. Marshall ◽  
Scott Cullen ◽  
Tahnee Saunders ◽  
Natalie J. Hannan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Mrna Expression ◽  
Vascular Dysfunction ◽  
Vascular Endothelial ◽  
Significant Difference ◽  
Show Evidence ◽  
Blood Pressures ◽  
Pregnant Mice ◽  
Renal Vascular ◽  
Endothelial Growth Factor

Pre-eclampsia (PE) is a leading cause of maternal and fetal death, characterised by an imbalance of placental growth factors and hypertension at >20 weeks gestation. Impaired maternal systemic vascular adaptations and fetal growth restriction are features of both PE and pregnant relaxin-deficient (Rln–/–) mice. The aim of the present study was to investigate whether these phenotypes in Rln–/– mice are associated with abnormal placental growth factor expression, increased soluble fms-like tyrosine kinase-1 (sFlt-1), proteinuria and/or hypertension during pregnancy. In addition, we examined relaxin and relaxin receptor (relaxin/insulin like family peptide receptor 1 (RXFP1)) mRNA expression in placentas of women with PE. There was no significant difference in placental vascular endothelial growth factor A (VegfA) and placenta growth factor (Plgf) gene expression between Rln–/– and wild-type mice. Circulating plasma sFlt-1 concentrations in pregnant mice of both genotypes and ages were increased compared with non-pregnant mice but were lower in younger pregnant Rln–/– mice compared with aged-matched Rln+/+ mice. Aged pregnant Rln–/– mice had higher urinary albumin : creatinine ratios compared with age-matched Rln+/+ mice, indicative of proteinuria. Systolic and diastolic blood pressures did not differ between genotypes. In addition, PE in women was not associated with altered placental mRNA expression of RLN2 or RXFP1 at term. Overall, the data demonstrate that pregnant Rln–/– mice do not have the typical characteristics of PE. However, these mice show evidence of proteinuria, but we suggest that this results from systemic renal vascular dysfunction before pregnancy.

scholarly journals Vascular Endothelial Growth Factor‐121 Administration Mitigates Halogen Inhalation‐Induced Pulmonary Injury and Fetal Growth Restriction in Pregnant Mice

2020 ◽  
Vol 9 (3) ◽  
Author(s):  
Dylan R. Addis ◽  
James A. Lambert ◽  
Changchun Ren ◽  
Stephen Doran ◽  
Saurabh Aggarwal ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Bronchoalveolar Lavage ◽  
Fetal Growth ◽  
Fetal Growth Restriction ◽  
Bronchoalveolar Lavage Fluid ◽  
Lavage Fluid ◽  
Vascular Endothelial ◽  
Pregnant Mice ◽  
Endothelial Growth Factor

Background Circulating levels of sFLT‐1 (soluble fms‐like tyrosine kinase 1), the extracellular domain of vascular endothelial growth factor (VEGF) receptor 1, and its ratio to levels of placental growth factor are markers of the occurrence and severity of preeclampsia. Methods and Results C57BL/6 pregnant mice on embryonic day 14.5 (E14.5), male, and non‐pregnant female mice were exposed to air or to Br 2 at 600 ppm for 30 minutes and were treated with vehicle or with VEGF‐121 (100 μg/kg, subcutaneously) daily, starting 48 hours post‐exposure. Plasma, bronchoalveolar lavage fluid, lungs, fetuses, and placentas were collected 120 hours post‐exposure. In Br 2 ‐exposed pregnant mice, there was a time‐dependent and significant increase in plasma levels of sFLT‐1 which correlated with increases in mouse lung wet/dry weights and bronchoalveolar lavage fluid protein content. Supplementation of exogenous VEGF‐121 improved survival and weight gain, reduced lung wet/dry weights, decreased bronchoalveolar lavage fluid protein levels, enhanced placental development, and improved fetal growth in pregnant mice exposed to Br 2 . Exogenous VEGF‐121 administration had no effect in non‐pregnant mice. Conclusions These results implicate inhibition of VEGF signaling driven by sFLT‐1 overexpression as a mechanism of pregnancy‐specific injury leading to lung edema, maternal mortality, and fetal growth restriction after bromine gas exposure.

scholarly journals COMMD1 upregulation is involved in copper efflux from ischemic hearts

2020 ◽  
pp. 153537022096984
Author(s):  
Chen Li ◽  
Tao Wang ◽  
Ying Xiao ◽  
Kui Li ◽  
Xia Meng ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Coronary Artery ◽  
Growth Factor ◽  
Contractile Function ◽  
Ischemic Myocardium ◽  
Ischemic Heart ◽  
Vascular Endothelial ◽  
Ischemic Infarction ◽  
Copper Loss ◽  
Endothelial Growth Factor

Copper depletion is associated with myocardial ischemic infarction, in which copper metabolism MURR domain 1 (COMMD1) is increased. The present study was undertaken to test the hypothesis that the elevated COMMD1 is responsible for copper loss from the ischemic myocardium, thus worsening myocardial ischemic injury. Mice (C57BL/6J) were subjected to left anterior descending coronary artery permanent ligation to induce myocardial ischemic infarction. In the ischemic myocardium, copper reduction was associated with a significant increase in the protein level of COMMD1. A tamoxifen-inducible, cardiomyocyte -specific Commd1 knockout mouse (C57BL/6J) model ( COMMD1CMC▲/▲) was generated using the Cre-LoxP recombination system. COMMD1CMC▲/▲ and wild-type littermates were subjected to the same permanent ligation of left anterior descending coronary artery. At the 7th day after ischemic insult, COMMD1 deficiency suppressed copper loss in the heart, along with preservation of vascular endothelial growth factor and vascular endothelial growth factor receptor 1 expression and the integrity of the vascular system in the ischemic myocardium. Corresponding to this change, infarct size of ischemic heart was reduced and myocardial contractile function was well preserved in COMMD1CMC▲/▲ mice. These results thus demonstrate that upregulation of COMMD1 is at least partially responsible for copper efflux from the ischemic heart. Cardiomyocyte-specific deletion of COMMD1 helps preserve the availability of copper for angiogenesis, thus suppressing myocardial ischemic dysfunction.

scholarly journals The role of progesterone in endometrial angiogenesis in pregnant and ovariectomised mice

Reproduction ◽  
2005 ◽  
Vol 129 (6) ◽  
pp. 765-777 ◽  
Author(s):  
Lisa M Walter ◽  
Peter A W Rogers ◽  
Jane E Girling
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Plasma Progesterone ◽  
Ovariectomized Mice ◽  
Pregnant Mice ◽  
Endothelial Growth Factor

The role of progesterone (and oestrogen) in endometrial angiogenesis remains controversial. The aims of this study were to quantify endometrial angiogenesis in pregnant mice and to investigate the role of progesterone in promoting endothelial cell proliferation in ovariectomized mice. Uteri were collected on days 1 to 4 of pregnancy when circulating progesterone concentrations were increasing, prior to implantation. Before dissection, mice were injected with bromodeoxyuridine (BrdU) enabling proliferating endothelial cells to be quantified with CD31/BrdU double-immunohistochemistry. There was a significant increase in proliferating endothelial cells on day 3 of pregnancy when plasma progesterone also increased. To determine if this endothelial cell proliferation was due to progesterone, an experiment was performed on ovariectomised mice. One group was treated with a single oestradiol injection on day 8 after ovariectomy, followed by a no-treatment day and three consecutive daily injections of progesterone. Other groups were treated with either the vehicle, oestradiol or progesterone injections only; all were dissected on day 13 following ovariectomy. Unexpectedly, mice treated with progesterone-only had the highest amount of endothelial cell proliferation and oestrogen priming was found to significantly reduce this progesterone-induced endothelial cell proliferation. To determine if this proliferation is mediated by vascular endothelial growth factor (VEGF), a further experiment in which VEGF anti-serum was administered concurrently with the progesterone injections was performed. Endothelial cell proliferation was reduced but not abolished suggesting progesterone-induced endometrial angiogenesis is only partly mediated by VEGF. Results indicate that oestrogen priming is not required for progesterone to stimulate endometrial endothelial cell proliferation and that oestrogen inhibits progesterone-induced angiogenesis in ovariectomised mice.

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