scholarly journals Acid Sensing Ion Channel 2a Is Reduced in the Reduced Uterine Perfusion Pressure Mouse Model and Increases Seizure Susceptibility in Pregnant Mice

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1135
Author(s):  
Maria Jones-Muhammad ◽  
Qingmei Shao ◽  
Loretta Cain-Shields ◽  
James P. Shaffery ◽  
Junie P. Warrington
Keyword(s):  
Perfusion Pressure ◽  
Respiratory Arrest ◽  
Wild Type ◽  
Seizure Duration ◽  
Drug Induced ◽  
Acid Sensing Ion Channels ◽  
Pregnant Mice ◽  
Uterine Perfusion ◽  
Drug Induced Seizures

Eclampsia is diagnosed in pregnant women who develop novel seizures. Our laboratory showed that the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia displays reduced latency to drug-induced seizures. While acid sensing ion channels (ASIC1a and 3) are important for reducing seizure longevity and severity, the role of ASIC2a in mediating seizure sensitivity in pregnancy has not been investigated. We hypothesized that 1) RUPP reduces hippocampal ASIC2a, and 2) pregnant mice with reduced ASIC2a (ASIC2a+/−) have increased seizure sensitivity. On gestational day 18.5, hippocampi from sham and RUPP C57BL/6 mice were harvested, and ASIC2a was assessed using Western blot. Pregnant wild-type and ASIC2a+/− mice received 40 mg/kg of pentylenetetrazol (i.p.) and were video recorded for 30 min. Behaviors were scored using a modified Racine scale (0–7: 0 = no seizure; 7 = respiratory arrest/death). Seizure severity was classified as mild (score = 1–3) or severe (score = 4–7). RUPP mice had reduced hippocampal and placental ASIC2a protein. ASIC2a+/− mice had reduced latency to seizures, increased seizure duration, increased severe seizure duration, and higher maximum seizure scores. Reduced hippocampal ASIC2a in RUPP mice and increased seizure activity in pregnant ASIC2a+/− mice support the hypothesis that reduced ASIC2a increases seizure sensitivity associated with the RUPP.

scholarly journals Reduced-Beclin1-Expressing Mice Infected with Zika-R103451 and Viral-Associated Pathology during Pregnancy

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 608 ◽  
Author(s):  
Mohan Kumar Muthu Karuppan ◽  
Chet Raj Ojha ◽  
Myosotys Rodriguez ◽  
Jessica Lapierre ◽  
M. Javad Aman ◽  
...  
Keyword(s):  
Growth Factor ◽  
Susceptibility Gene ◽  
Neuronal Loss ◽  
Wild Type ◽  
Zikv Infection ◽  
Expression Levels ◽  
Pregnant Mice ◽  
Alpha Beta ◽  
Inflammatory Molecules

Here, we used a mouse model with defective autophagy to further decipher the role of Beclin1 in the infection and disease of Zika virus (ZIKV)-R103451. Hemizygous (Becn1+/−) and wild-type (Becn1+/+) pregnant mice were transiently immunocompromised using the anti-interferon alpha/beta receptor subunit 1 monoclonal antibody MAR1-5A3. Despite a low mortality rate among the infected dams, 25% of Becn1+/− offspring were smaller in size and had smaller, underdeveloped brains. This phenotype became apparent after 2-to 3-weeks post-birth. Furthermore, the smaller-sized pups showed a decrease in the mRNA expression levels of insulin-like growth factor (IGF)-1 and the expression levels of several microcephaly associated genes, when compared to their typical-sized siblings. Neuronal loss was also noticeable in brain tissues that were removed postmortem. Further analysis with murine mixed glia, derived from ZIKV-infected Becn1+/− and Becn1+/+ pups, showed greater infectivity in glia derived from the Becn1+/− genotype, along with a significant increase in pro-inflammatory molecules. In the present study, we identified a link by which defective autophagy is causally related to increased inflammatory molecules, reduced growth factor, decreased expression of microcephaly-associated genes, and increased neuronal loss. Specifically, we showed that a reduced expression of Beclin1 aggravated the consequences of ZIKV infection on brain development and qualifies Becn1 as a susceptibility gene of ZIKV congenital syndrome.

scholarly journals Melanocortin-4 Receptor Deficiency Attenuates Placental Ischemia-Induced Hypertension in Pregnant Rats

Hypertension ◽  
2019 ◽  
Vol 73 (1) ◽  
pp. 162-170 ◽  
Author(s):  
Frank T. Spradley ◽  
Ana C. Palei ◽  
Christopher D. Anderson ◽  
Joey P. Granger
Keyword(s):  
Blood Pressure ◽  
Nervous System ◽  
Perfusion Pressure ◽  
Wild Type ◽  
Pregnant Rats ◽  
Melanocortin 4 Receptor ◽  
Induced Hypertension ◽  
Sympathetic Nervous ◽  
Uterine Perfusion ◽  
Placental Ischemia

Preeclampsia is a pregnancy-specific disorder of new-onset hypertension linked to placental ischemia. While obesity is a major risk factor for preeclampsia, not all obese pregnant women develop pregnancy-induced hypertension or preeclampsia. Previously, we reported that placental ischemia-induced hypertension is dependent upon intact signaling of the sympathetic nervous system. Moreover, in various models of obesity, blockade of MC4R (melanocortin-4 receptor) signaling protects against the development of hypertension via suppression of the sympathetic nervous system. Less is known about this pathway during obese pregnancy. Although blockade of MC4R may lead to increased body weight during pregnancy, we tested the hypothesis that placental ischemia-induced hypertension is attenuated in obese MC4R-deficient pregnant rats. On gestational day 14, MC4R wild-type or heterozygous-deficient (MC4R-def) rats were subjected to chronic placental ischemia via the reduced uterine perfusion pressure procedure or Sham surgery then examined on gestational day 19. In Sham MC4R-def versus Sham wild-type pregnant rats, there was increased body weight, fat mass, and circulating leptin levels but they had similar fetus weights. Reduced uterine perfusion pressure reduced fetus weights in both strains. Reduced uterine perfusion pressure increased blood pressure in wild-type rats but this response was significantly attenuated in MC4R-def rats, although blood pressure was elevated in Sham MC4R-def over Sham wild-type. These data indicate that while obese MC4R-def pregnant rats have higher blood pressure during pregnancy, placental ischemia-induced hypertension is attenuated in obese MC4R-def pregnant rats. Thus, obese women with abnormal MC4R signaling may be less susceptible to the development of placental ischemia-induced hypertension.

scholarly journals Adenosine A2A receptors in early ischemic vascular injury after subarachnoid hemorrhage

2010 ◽  
Vol 113 (4) ◽  
pp. 826-834 ◽  
Author(s):  
Fatima A. Sehba ◽  
Rowena Flores ◽  
Artur Muller ◽  
Victor Friedrich ◽  
Jiang-Fan Chen ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Knockout Mice ◽  
Cerebral Perfusion ◽  
Type Iv Collagen ◽  
Perfusion Pressure ◽  
Internal Diameter ◽  
Vascular Response ◽  
Wild Type ◽  
Type Iv

Object The role of adenosine A2A receptors in the early vascular response after subarachnoid hemorrhage (SAH) is unknown. In other forms of cerebral ischemia both activation and inhibition of A2A receptors is reported to be beneficial. However, these studies mainly used pharmacological receptor modulation, and most of the agents available exhibit low specificity. The authors used adenosine A2A receptor knockout mice to study the role of A2A receptors in the early vascular response to SAH. Methods Subarachnoid hemorrhage was induced in wild-type mice (C57BL/6) and A2A receptor knockout mice by endovascular puncture. Cerebral blood flow, intracranial pressure, and blood pressure were recorded, and cerebral perfusion pressure was deduced. Animals were sacrificed at 1, 3, or 6 hours after SAH or sham surgery. Coronal brain sections were immunostained for Type IV collagen, the major protein of the basal lamina. The internal diameter of major cerebral arteries and the area fraction of Type IV collagen–positive microvessels (< 100 μm) were determined. Results The initial increase in intracranial pressure and decrease in cerebral perfusion pressure at SAH induction was similar in both types of mice, but cerebral blood flow decline was significantly smaller in A2A receptor knockout mice as compared with wild-type cohorts. The internal diameter of major cerebral vessels decreased progressively after SAH. The extent of diameter reduction was significantly less in A2A receptor knockout mice than in wild-type mice. Type IV collagen immunostaining decreased progressively after SAH. This decrease was significantly less in A2A receptor knockout mice than in wild-type mice. Conclusions These results demonstrate that global inactivation of A2A receptors decreases the intensity of the early vascular response to SAH. Early inhibition of A2A receptors after SAH might reduce cerebral injury.

scholarly journals Role of Mitochondrial Dysfunction and Reactive Oxygen Species in Mediating Hypertension in the Reduced Uterine Perfusion Pressure Rat Model of Preeclampsia

Hypertension ◽  
2018 ◽  
Vol 72 (3) ◽  
pp. 703-711 ◽  
Author(s):  
Venkata Ramana Vaka ◽  
Kristen M. McMaster ◽  
Mark W. Cunningham ◽  
Tarek Ibrahim ◽  
Rebekah Hazlewood ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Mitochondrial Dysfunction ◽  
Rat Model ◽  
Perfusion Pressure ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Uterine Perfusion

Cleavage of Bax to p18 Bax accelerates stress-induced apoptosis, and a cathepsin-like protease may rapidly degrade p18 Bax

Blood ◽  
2003 ◽  
Vol 102 (7) ◽  
pp. 2605-2614 ◽  
Author(s):  
Xuefang Cao ◽  
Xingming Deng ◽  
W. Stratford May
Keyword(s):  
Expression System ◽  
Wild Type ◽  
Mitochondrial Membranes ◽  
Caspase 9 ◽  
Cytochrome C Release ◽  
Drug Induced ◽  
293 Cells ◽  
Increased Sensitivity ◽  
Induced Apoptosis

Abstract Bax is cleaved by calpain at aspartate 33 (Asp33) to yield p18 Bax during stress-induced apoptosis. To assess the role of p18 Bax in apoptosis, an ecdysone-inducible expression system was generated. Similar levels of wild-type (WT) and noncleavable Asp33Ala (Asp→Ala) Bax are induced in 293 cells while expression of N-terminal-deleted p18 (Δ1-33) Bax remains low (20% of full-length p21 Bax) due to a reduced half-life (2 hours versus 12 hours for p21 Bax) resulting from increased sensitivity to cathepsin-like proteolytic degradation. Expression of p18 Bax is enhanced to levels comparable to p21 Bax when induction is carried out in the presence of cathepsin inhibitors, Z-Phe-Gly-NHO-Bz or N-Acetyl-Leu-Leu-Met-CHO. Compared with WT Bax, expression of similar levels of p18 Bax and, surprisingly, Asp33Ala Bax more potently induces apoptosis as indicated by increased cytochrome c release, caspase-9/-3 activation, and DNA fragmentation, potentially due to their increased homo-oligomerization in mitochondrial membranes. Studies in A-549, U-937, K-562, and HL-60 cells confirm that inhibition of Bax cleavage results in 25% to 35% reduction of drug-induced apoptosis, while inhibition of p18 Bax degradation enhances apoptosis by 25% to 40%. Results indicate that although cleavage to p18 Bax is not required for Bax to initiate apoptosis, p18 Bax potently accelerates the apoptotic process. (Blood. 2003;102:2605-2614)

scholarly journals Nicotinamide ameliorates a preeclampsia-like condition in mice with reduced uterine perfusion pressure

2017 ◽  
Vol 312 (2) ◽  
pp. F366-F372 ◽  
Author(s):  
Tomofumi Fushima ◽  
Akiyo Sekimoto ◽  
Yuji Oe ◽  
Emiko Sato ◽  
Sadayoshi Ito ◽  
...  
Keyword(s):  
Perfusion Pressure ◽  
Reduce Blood Pressure ◽  
Vitamin B ◽  
Therapeutic Effects ◽  
Pregnancy Induced Hypertension ◽  
Induced Hypertension ◽  
Maternal Hypertension ◽  
Pregnant Mice ◽  
Survival And Growth ◽  
Uterine Perfusion

Preeclampsia (PE) is pregnancy-induced hypertension with proteinuria that typically develops after 20 wk of gestation. Antihypertensives currently used for PE reduce blood pressure of PE mothers but do not prevent preterm delivery and do not alleviate fetal growth restriction (FGR) associated with PE. We have recently shown that the activation of the endothelin (ET) system exacerbates PE. However, ET receptor antagonists are teratogenic and not suitable for pregnant women. The vitamin B3 nicotinamide (Nam) inhibits vasoconstriction by ET and is generally considered safe and harmless to babies. Nam also alleviates oxidative stress, which exacerbates PE and FGR. The aim of the present study was to evaluate therapeutic effects of Nam on the PE-like phenotype using a reduced uterine perfusion pressure (RUPP) model in mice that we have recently developed. We bilaterally ligated uterine vessels of pregnant mice and administered Nam or water daily by gavage. Nam improved maternal hypertension, proteinuria, and glomerular endotheliosis in RUPP mice. Moreover, Nam prolonged pregnancies and improved survival and growth of the embryos in RUPP PE mice. In conclusion, Nam alleviates the PE-like phenotype and FGR in the murine RUPP model. Nam could help treat maternal hypertension and FGR in human PE.

scholarly journals Role of Peroxiredoxin III in the Pathogenesis of Pre-eclampsia as Evidenced in Mice

2010 ◽  
Vol 3 (1) ◽  
pp. 71-73 ◽  
Author(s):  
Lianqin Li ◽  
Masuo Obinata ◽  
Katsuyoshi Hori
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Reactive Oxygen Species ◽  
Knockout Mice ◽  
Oxidative Status ◽  
Intracellular Reactive Oxygen Species ◽  
Oxygen Species ◽  
Wild Type ◽  
Pregnant Mice

As a member of peroxiredoxin (Prx) family, PrxIII has been demonstrated to play an important role in scavenging intracellular reactive oxygen species (ROS). Since PrxIII knockout mice exhibited oxidative stress in placentas resembling pathophysiologic changes in placentas of human pre-eclampsia, we measured blood pressure through the carotid artery and detected oxidative status by western blotting in pregnant mice. We did not notice hypertension in pregnant PrxIII knockout mice as compared with wild-type littermates, although endothelin-1 was overexpressed in PrxIII-deficient placentas. Our results indicate that PrxIII is not involved in pre-eclamptic development. Instead, PrxIII is an indispensable antioxidant in placentas where oxidative stress exists.

Role of angiotensin II and prostaglandins in the regulation of uteroplacental blood flow

1993 ◽  
Vol 264 (3) ◽  
pp. R584-R590 ◽  
Author(s):  
L. L. Woods
Keyword(s):  
Blood Flow ◽  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Perfusion Pressure ◽  
Moderate Degree ◽  
Ang Ii ◽  
Response Curves ◽  
Uteroplacental Blood Flow ◽  
Uterine Perfusion

This study was designed to determine the importance of the renin-angiotensin (RAS) and prostaglandin (PG) systems in regulating uteroplacental blood flow (UBF). Our objectives were to determine: 1) whether angiotensin II (ANG II) acts as a vasodilator or purely as a vasoconstrictor in the uteroplacental circulation, and 2) whether this circulation is capable of autoregulation. In chronically instrumented pregnant dogs (41-54 days gestation), ANG II was infused intravenously at increasing doses (8, 16, and 24 ng.kg-1 x min-1). Arterial pressure rose from 108 +/- 6 to 146 +/- 4 mmHg and UBF did not change but uterine vascular resistance (UVR) progressively increased. When the experiment was repeated while servo-controlling uterine arterial pressure, UBF fell at all doses, reaching 62 +/- 7% of control at the highest dose, and UVR increased as before. Meclofenamate (6 mg/kg i.v.) did not alter the dose-response curves. In separate experiments, uterine perfusion pressure was reduced in steps to 55 mmHg. UBF was well autoregulated down to approximately 85 mmHg, and neither captopril (14 micrograms.kg-1 x min-1) nor meclofenamate altered UBF autoregulation. Thus ANG II appears to act as a vasoconstrictor in the uteroplacental circulation and any preservation of UBF during ANG II appears to be due to the increased arterial pressure. Also, in the dog the uteroplacental circulation possesses a mild to moderate degree of autoregulatory capability, which does not appear to be dependent on the RAS or PGs.

Differential Role of Components of the Fibrinolytic System in the Formation and Removal of Thrombus Induced by Endothelial Injury

1999 ◽  
Vol 81 (04) ◽  
pp. 601-604 ◽  
Author(s):  
Hiroyuki Matsuno ◽  
Osamu Kozawa ◽  
Masayuki Niwa ◽  
Shigeru Ueshima ◽  
Osamu Matsuo ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Thrombus Formation ◽  
Endothelial Injury ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Clot Lysis ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Pai 1

SummaryThe role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4 ± 1.3, 9.8 ± 1.1 or 9.7 ± 1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (18.4 ± 3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.

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