Common arterial trunk and ventricular non-compaction in Lrp2 knockout mice indicate a crucial role of LRP2 in cardiac development

Lipoprotein-related receptor protein 2 (LRP2) is important for development of the embryonic neural crest and brain in both mice and humans. Although a role in cardiovascular development can be expected, the hearts of Lrp2 knockout (KO) mice have not yet been investigated. We studied the cardiovascular development of Lrp2 KO mice between embryonic day 10.5 (E10.5) and E15.5, applying morphometry and immunohistochemistry, using antibodies against Tfap2α (neural crest cells), Nkx2.5 (second heart field), WT1 (epicardium derived cells), tropomyosin (myocardium) and LRP2. The Lrp2 KO mice display a range of severe cardiovascular abnormalities, including aortic arch anomalies, common arterial trunk (persistent truncus arteriosus) with coronary artery anomalies, ventricular septal defects, overriding of the tricuspid valve and marked thinning of the ventricular myocardium. Both the neural crest cells and second heart field, which are essential for the lengthening and growth of the right ventricular outflow tract, are abnormally positioned in the Lrp2 KO. T hi s explains the absence of the aorto-pulmonary septum, which leads to common arterial trunk and ventricular septal defects. Severe blebbing of the epicardial cells covering the ventricles is seen. Epithelial-mesenchymal transition does occur; however, there are fewer WT1-positive epicardium-derived cells in the ventricular wall as compared to normal, coinciding with the myocardial thinning and deep intertrabecular spaces. LRP2 plays a crucial role in cardiovascular development in mice. This corroborates findings of cardiac anomalies in humans with LRP2 mutations. Future studies should reveal the underlying signaling mechanisms in which LRP2 is involved during cardiogenesis

Epigenetics in the primary and secondary prevention of cardiovascular disease: influence of exercise and nutrition

Increasing evidence links changes in epigenetic systems, such as DNA methylation, histone modification, and non-coding RNA expression, to the occurrence of cardiovascular disease (CVD). These epigenetic modifications can change genetic function under influence of exogenous stimuli and can be transferred to next generations, providing a potential mechanism for inheritance of behavioural intervention effects. The benefits of exercise and nutritional interventions in the primary and secondary prevention of CVD are well established, but the mechanisms are not completely understood. In this review, we describe the acute and chronic epigenetic effects of physical activity and dietary changes. We propose exercise and nutrition as potential triggers of epigenetic signals, promoting the reshaping of transcriptional programmes with effects on CVD phenotypes. Finally, we highlight recent developments in epigenetic therapeutics with implications for primary and secondary CVD prevention

Developmental programming in human umbilical cord vein endothelial cells following fetal growth restriction

Background: Fetal growth restriction (FGR) is associated with an increased susceptibility for various noncommunicable diseases in adulthood, including cardiovascular and renal disease. During FGR, reduced uteroplacental blood flow, oxygen and nutrient supply to the fetus are hypothesized to detrimentally influence cardiovascular and renal programming. This study examined whether developmental programming profiles, especially related to the cardiovascular and renal system, differ in human umbilical vein endothelial cells (HUVECs) collected from pregnancies complicated by placental insufficiency-induced FGR compared to normal growth pregnancies. Our approach, involving transcriptomic profiling by RNA-sequencing and gene set enrichment analysis focused on cardiovascular and renal gene sets and targeted DNA methylation assays, contributes to the identification of targets underlying long-term cardiovascular and renal diseases. Results: Gene set enrichment analysis showed several downregulated gene sets, most of them involved in immune or inflammatory pathways or cell cycle pathways. seven of the 22 significantly upregulated gene sets related to kidney development and four gene sets involved with cardiovascular health and function were downregulated in FGR (n = 11) versus control (n = 8). Transcriptomic profiling by RNA-sequencing revealed downregulated expression of LGALS1, FPR3 and NRM and upregulation of lincRNA RP5-855F14.1 in FGR compared to controls. DNA methylation was similar for LGALS1 between study groups, but relative hypomethylation of FPR3 and hypermethylation of NRM were present in FGR, especially in male offspring. Absolute differences in methylation were, however, small. Conclusion: This study showed upregulation of gene sets related to renal development in HUVECs collected from pregnancies complicated by FGR compared to control donors. The differentially expressed gene sets related to cardiovascular function and health might be in line with the downregulated expression of NRM and upregulated expression of lincRNA RP5-855F14.1 in FG

Epigenetics in the primary and secondary prevention of cardiovascular disease:influence of exercise and nutrition

Increasing evidence links changes in epigenetic systems, such as DNA methylation, histone modification and non-coding RNA expression, to the occurrence of cardiovascular disease (CVD). These epigenetic modifications can change genetic function under influence of exogenous stimuli, and can be transferred to next generations, providing a potential mechanism for inheritance of behavioral intervention effects. The benefits of exercise and nutritional interventions in the primary and secondary prevention of CVD are well established, but the mechanisms are not completely understood. In this review, we describe the acute and chronic epigenetic effects of physical activity and dietary changes. We propose exercise and nutrition as potential triggers of epigenetic signals, promoting the reshaping of transcriptional programs with effects on CVD phenotypes. Finally, we highlight recent developments in epigenetic therapeutics with implications for primary and secondary CVD prevention.</p

Maternal diet-induced profiles of liver gene expression and biological functions.

<p>(A) PCA was performed with the top 1,000 most variable genes (based on IQR) of the microarray analysis. (B) The gene expression response (displayed as 2log-ratio of maternal WSD-maternal LFD) of male and female offspring is plotted against each other. (C) By maternal WSD significantly up- or down-regulated genes (<i>p</i>≤0.01) are shown for male and female offspring. (D) Significantly up- or down-regulated genes (<i>p</i>≤0.01) in both sexes were compared and are shown as Venn diagrams. (E) and (F) Ingenuity Pathway Analysis (IPA) was carried out on genes that were significantly differentially expressed upon maternal WSD. The top 25 regulated biological functions in males and females respectively, are displayed. Hatched bars = biological functions that occur in the top 25 of both sexes. Filled bars = biological functions that are specific for one sex. Sys = System.</p

Lipid metabolism in offspring of maternal WSD represented by sub-functions and heat maps.

<p>(A) and (B) display sub-functions of lipid-metabolism that were according to IPA significantly regulated (<i>p</i>≤0.05) upon maternal WSD in males or females respectively and contained≥7 regulated molecules. Hatched bars = sub-functions that are regulated in both sexes. Filled bars = sub-functions that are specific for the sex. Syn = Synthesis; Conc = Concentration; Metab = Metabolism; Transp = Transport; Accu = Accumulation; Terp = Terpenoid; Cho = Cholesterol; DAG = Diacylglycerol; FA = Fatty Acid. (C) and (D) show hierarchical clustered heat maps of the fatty acid metabolism gene set and the cholesterol metabolism gene set, respectively. Hierarchical clustering of gene sets was based on Pearson correlation. Gene expression values are displayed on colour scale: blue indicates lower values than average of maternal LFD-group of respective sex; orange indicates higher values than average of maternal LFD-group of respective sex. (m) = gene was significantly changed in male offspring upon maternal WSD. (f) = gene was significantly changed in female offspring upon maternal WSD. <i>p</i>-values≤0.01 were considered significant.</p

Heat map of Wnt/beta-catenin pathway.

<p>The Wnt/beta-catenin gene set was hierarchically clustered based on Pearson correlation. Gene expression values are displayed on colour scale: blue indicates lower values than average of maternal LFD-group of respective sex; orange indicates higher values than average of maternal LFD-group of respective sex. (m) = gene was significantly changed in male offspring upon maternal WSD. (f) = gene was significantly changed in female offspring upon maternal WSD. <i>p</i>-values≤0.01 were considered significant.</p

Study design.

<p>C57BL/6 dams received either a low fat control diet (LFD) or a Western-style high fat diet (WSD) throughout the study. The treatment started six weeks before mating and continued during gestation and lactation. Dams and offspring were sacrificed at postnatal week two. Male and female offspring were included into further analysis: male offspring from maternal LFD (n = 6), male offspring from maternal WSD (n = 6), female offspring from maternal LFD (n = 9), female offspring from maternal WSD (n = 6).</p

Physiological parameters in dams fed LFD or WSD at two weeks post-delivery.

*<p><i>p</i>-value≤0.05; ** <i>p</i>-value≤0.01</p

Endothelium-Dependent Relaxation and Angiotensin II Sensitivity in Experimental Preeclampsia

<p>Objective: We investigated endothelial dysfunction and the role of angiotensin (Ang)-II type I (AT1-R) and type II (AT2-R) receptor in the changes in the Ang-II sensitivity in experimental preeclampsia in the rat.</p><p>Methods: Aortic rings were isolated from low dose lipopolysaccharide (LPS) infused pregnant rats (experimental preeclampsia; n=9), saline-infused pregnant rats (n=8), and saline (n=8) and LPS (n=8) infused non-pregnant rats. Endothelium-dependent acetylcholine--mediated relaxation was studied in phenylephrine-preconstricted aortic rings in the presence of vehicle, N-G-nitro-L-arginine methyl ester and/or indomethacin. To evaluate the role for AT1-R and AT2-R in Ang-II sensitivity, full concentration response curves were obtained for Ang-II in the presence of losartan or PD123319. mRNA expression of the AT1-R and AT2-R, eNOS and iNOS, COX1 and COX2 in aorta were evaluated using real-time RT-PCR.</p><p>Results: The role of vasodilator prostaglandins in the aorta was increased and the role of endothelium-derived hyperpolarizing factor and response of the AT1-R and AT2-R to Ang-II was decreased in pregnant saline infused rats as compared with non-pregnant rats. These changes were not observed during preeclampsia.</p><p>Conclusion: Pregnancy induced adaptations in endothelial function, which were not observed in the rat model for preeclampsia. This role of lack of pregnancy induced endothelial adaptation in the pathophysiology of experimental preeclampsia needs further investigation.</p>