scholarly journals Stimulation of Soluble Guanylate Cyclase Diminishes Intrauterine Growth Restriction in a Rat Model of Placental Ischemia

2020 ◽  
Author(s):  
Laura E. Coats ◽  
Daniel R. Bamrick-Fernandez ◽  
Allison M. Ariatti ◽  
Bhavisha A. Bakrania ◽  
Adam Z. Rawls ◽  
...  
Keyword(s):  
Protein Expression ◽  
Guanylate Cyclase ◽  
Rat Model ◽  
Intrauterine Growth Restriction ◽  
Soluble Guanylate Cyclase ◽  
Junctional Zone ◽  
Placental Perfusion ◽  
Intrauterine Growth ◽  
Placental Ischemia ◽  
Stimulation Of

Placental ischemia in preeclampsia (PE) results in hypertension and intrauterine growth restriction (IUGR). Stimulation of soluble guanylate cyclase (sGC) reduces blood pressure in the clinically relevant reduced uterine perfusion pressure (RUPP) rat model of PE implicating involvement in RUPP-induced hypertension. However, the contribution of sGC in the development of IUGR in PE is not known. Thus, this study demonstrated the efficacy of Riociguat, a sGC stimulator, in IUGR reversion in the RUPP rat model of PE, and tested the hypothesis that improvement in fetal weight occurs in association with improvement in placental perfusion, placental morphology, and placental nutrient transport protein expression. Sham or RUPP surgery was performed at gestational day 14 (G14) with administration of vehicle (Sham or RUPP) or the sGC stimulator (Riociguat, 10mg/kg/day, s.c.) (sGC-treated) until G20. Fetal weight was reduced (p=0.004) at G20 in RUPP but not sGC-treated RUPP compared to Sham, the control group. At G20, uterine artery resistance index (UARI) was increased (p=0.010) in RUPP indicating poor placental perfusion; proportional junctional zone surface area was elevated (p=0.035) indicating impaired placental development. These effects were ameliorated in sGC-treated RUPP. Placental protein expression of nutrient transporter heart fatty acid binding protein (hFABP) was increased (p=0.008) in RUPP but not sGC-treated RUPP suggesting a compensatory mechanism to maintain normal neurodevelopment. Yet, UARI (p<0.001), proportional junctional zone surface area (p=0.013), and placental hFABP protein expression (p=0.008) were increased in sGC-treated Sham suggesting a potential adverse effect of Riociguat. Collectively, these results suggest sGC contributes to IUGR in PE.

Soluble guanylate cyclase stimulation in late gestation does not mitigate asymmetric IUGR or cardiovascular risk induced by placental ischemia in the rat

2021 ◽  
Author(s):  
Laura E. Coats ◽  
Bhavisha A. Bakrania ◽  
Daniel R Bamrick-Fernandez ◽  
Allison M. Ariatti ◽  
Adam Z. Rawls ◽  
...  
Keyword(s):  
Cardiovascular Risk ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Global Longitudinal Strain ◽  
Growth Restriction ◽  
Abdominal Circumference ◽  
Gestational Length ◽  
Intrauterine Growth ◽  
Placental Ischemia ◽  
Stimulation Of

Stimulation of soluble guanylate cyclase (sGC) improves fetal growth at gestational day 20 in the reduced uterine perfusion pressure (RUPP) rat model of placental ischemia suggesting a role for sGC in the etiology of intrauterine growth restriction (IUGR). This study tested the hypothesis that stimulation of sGC until birth attenuates asymmetric IUGR mitigating increased cardiovascular risk in offspring. Sham or RUPP surgery was performed at gestational day 14 (G14); vehicle or sGC stimulator, Riociguat (10mg/kg/day, s.c.) were administered G14 until birth. Birth weight was reduced in offspring from RUPP (intrauterine growth restricted or IUGR), sGC RUPP (sGC IUGR), and sGC Sham (sGC Control) compared to Sham (Control). Crown circumference was maintained but abdominal circumference was reduced in IUGR and sGC IUGR compared to Control indicative of asymmetrical growth. Gestational length was prolonged in sGC RUPP, and survival at birth was reduced in sGC IUGR. Probability of survival to postnatal day 2 was also significantly reduced in IUGR and sGC IUGR versus Control, and in sGC IUGR versus IUGR. At 4 months of age blood pressure was increased in male IUGR and sGC IUGR, but not male sGC Control born with symmetrical IUGR. Global longitudinal strain was increased and stroke volume was decreased in male IUGR and sGC IUGR compared to Control. Thus, late gestational stimulation of sGC does not mitigate asymmetric IUGR or increased cardiovascular risk in male sGC IUGR. Furthermore, late gestational stimulation of sGC is associated with symmetrical growth restriction in sGC Control implicating contraindications in normal pregnancy.

scholarly journals Endothelial Colony-Forming Cells Dysfunctions Are Associated with Arterial Hypertension in a Rat Model of Intrauterine Growth Restriction

2021 ◽  
Vol 22 (18) ◽  
pp. 10159
Author(s):  
Stephanie Simoncini ◽  
Hanna Coppola ◽  
Angela Rocca ◽  
Isaline Bachmann ◽  
Estelle Guillot ◽  
...  
Keyword(s):  
Protein Expression ◽  
Arterial Hypertension ◽  
Rat Model ◽  
Intrauterine Growth Restriction ◽  
Growth Restriction ◽  
Sirtuin 1 ◽  
Brdu Incorporation ◽  
Intrauterine Growth ◽  
Endothelial Colony Forming Cells ◽  
Stress Induced Premature Senescence

Infants born after intrauterine growth restriction (IUGR) are at risk of developing arterial hypertension at adulthood. The endothelium plays a major role in the pathogenesis of hypertension. Endothelial colony-forming cells (ECFCs), critical circulating components of the endothelium, are involved in vasculo-and angiogenesis and in endothelium repair. We previously described impaired functionality of ECFCs in cord blood of low-birth-weight newborns. However, whether early ECFC alterations persist thereafter and could be associated with hypertension in individuals born after IUGR remains unknown. A rat model of IUGR was induced by a maternal low-protein diet during gestation versus a control (CTRL) diet. In six-month-old offspring, only IUGR males have increased systolic blood pressure (tail-cuff plethysmography) and microvascular rarefaction (immunofluorescence). ECFCs isolated from bone marrow of IUGR versus CTRL males displayed a decreased proportion of CD31+ versus CD146+ staining on CD45− cells, CD34 expression (flow cytometry, immunofluorescence), reduced proliferation (BrdU incorporation), and an impaired capacity to form capillary-like structures (Matrigel test), associated with an impaired angiogenic profile (immunofluorescence). These dysfunctions were associated with oxidative stress (increased superoxide anion levels (fluorescent dye), decreased superoxide dismutase protein expression, increased DNA damage (immunofluorescence), and stress-induced premature senescence (SIPS; increased beta-galactosidase activity, increased p16INK4a, and decreased sirtuin-1 protein expression). This study demonstrated an impaired functionality of ECFCs at adulthood associated with arterial hypertension in individuals born after IUGR.

Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models

2010 ◽  
Vol 28 (8) ◽  
pp. 1666-1675 ◽  
Author(s):  
Yuliya Sharkovska ◽  
Philipp Kalk ◽  
Bettina Lawrenz ◽  
Michael Godes ◽  
Linda Sarah Hoffmann ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Organ Damage ◽  
Stimulation Of

scholarly journals Acute stimulation of the soluble guanylate cyclase does not impact on left ventricular capacitance in normal and hypertrophied porcine hearts in vivo

2018 ◽  
Vol 315 (3) ◽  
pp. H669-H680 ◽  
Author(s):  
Alessio Alogna ◽  
Michael Schwarzl ◽  
Martin Manninger ◽  
Nazha Hamdani ◽  
Birgit Zirngast ◽  
...  
Keyword(s):  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Diastolic Pressure ◽  
Aortic Pressure ◽  
Left Ventricular ◽  
Concentric Hypertrophy ◽  
Ventricular Compliance ◽  
Left Ventricular Compliance ◽  
Stimulation Of

Experimental data indicate that stimulation of the nitric oxide-soluble guanylate cyclase(sGC)-cGMP-PKG pathway can increase left ventricular (LV) capacitance via phosphorylation of the myofilamental protein titin. We aimed to test whether acute pharmacological sGC stimulation with BAY 41-8543 would increase LV capacitance via titin phosphorylation in healthy and deoxycorticosteroneacetate (DOCA)-induced hypertensive pigs. Nine healthy Landrace pigs and 7 pigs with DOCA-induced hypertension and LV concentric hypertrophy were acutely instrumented to measure LV end-diastolic pressure-volume relationships (EDPVRs) at baseline and during intravenous infusion of BAY 41-8543 (1 and 3 μg·kg−1·min−1 for 30 min, respectively). Separately, in seven healthy and six DOCA pigs, transmural LV biopsies were harvested from the beating heart to measure titin phosphorylation during BAY 41-8543 infusion. LV EDPVRs before and during BAY 41-8543 infusion were superimposable in both healthy and DOCA-treated pigs, whereas mean aortic pressure decreased by 20–30 mmHg in both groups. Myocardial titin phosphorylation was unchanged in healthy pigs, but total and site-specific (Pro-Glu-Val-Lys and N2-Bus domains) titin phosphorylation was increased in DOCA-treated pigs. Bicoronary nitroglycerin infusion in healthy pigs ( n = 5) induced a rightward shift of the LV EDPVR, demonstrating the responsiveness of the pathway in this model. Acute systemic sGC stimulation with the sGC stimulator BAY 41-8543 did not recruit an LV preload reserve in both healthy and hypertrophied LV porcine myocardium, although it increased titin phosphorylation in the latter group. Thus, increased titin phosphorylation is not indicative of increased in vivo LV capacitance. NEW & NOTEWORTHY We demonstrate that acute pharmacological stimulation of soluble guanylate cyclase does not increase left ventricular compliance in normal and hypertrophied porcine hearts. Effects of long-term soluble guanylate cyclase stimulation with oral compounds in disease conditions associated with lowered myocardial cGMP levels, i.e., heart failure with preserved ejection fraction, remain to be investigated.

scholarly journals Evidence from human placenta, ER-stressed trophoblasts and transgenic mice links transthyretin proteinopathy to preeclampsia

2022 ◽  
Author(s):  
Shibin Cheng ◽  
Zheping Huang ◽  
Sayani Banerjee ◽  
Joel Buxbaum ◽  
Surendra Sharma
Keyword(s):  
Transgenic Mice ◽  
Intrauterine Growth Restriction ◽  
Caspase 3 ◽  
Kidney Injury ◽  
Wild Type ◽  
Junctional Zone ◽  
Intrauterine Growth ◽  
Pregnant Mice ◽  
Umbilical Arteries ◽  
Trophoblast Cell Line

We have demonstrated that protein aggregation plays a pivotal role in the pathophysiology of preeclampsia (PE) and identified several aggregated proteins in the circulation of PE patients, most significantly the serum protein transthyretin (TTR). Here we show robust accumulation of TTR aggregates in the placentas of women with early-onset PE (e-PE). TTR aggregation was inducible in primary human trophoblasts (PHTs) and the TCL-1 trophoblast cell line by ER stress inducers or autophagy-lysosomal disruptors. Hypoxia/reoxygenation (H/R) of cultured PHTs increased intracellular BiP, phosphorylated IRE1alpha, PDI and Ero-1, all markers of the UPR, and the apoptosis mediator caspase-3. Blockade of IRE1alpha inhibited H/R-induced upregulation of Ero-1 in PHTs. Excessive UPR was observed in the PE placenta. Further, pregnant mice, overexpressing transgene encoded wild type human TTR, displayed aggregated TTR in the junctional zone of the placenta and PE-like features including hypertension, proteinuria, intrauterine growth restriction, kidney injury, and elevated levels of the PE biomarkers serum sFlt-1 and endoglin. High Resolution Ultrasound analysis revealed low blood flow in uterine and umbilical arteries compared to that found in wild type pregnant mice. On the other hand, loss of mouse TTR function did not cause any pregnancy abnormalities in Ttr-/- mice. These observations in the PE placenta, cultured trophoblast cells and TTR transgenic mice indicate that TTR aggregation is an important causal contributor to PE pathophysiology.

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