scholarly journals Hypertension in response to CD4+ T cells from reduced uterine perfusion pregnant rats is associated with activation of the endothelin-1 system

2012 ◽  
Vol 303 (2) ◽  
pp. R144-R149 ◽  
Author(s):  
Kedra Wallace ◽  
Sarah Novotny ◽  
Judith Heath ◽  
Janae Moseley ◽  
James N. Martin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Transfer ◽  
Rat Serum ◽  
Pregnant Rats ◽  
Endothelin 1 ◽  
Induced Hypertension ◽  
Uterine Perfusion ◽  
Placental Ischemia

We have shown that adoptive transfer of CD4+ T cells from placental ischemia (reduction in uteroplacental perfusion, RUPP) rats causes hypertension and elevated inflammatory cytokines during pregnancy. In this study we tested the hypothesis that adoptive transfer of RUPP CD4+ T cells was associated with endothelin-1 activation as a mechanism to increase blood pressure during pregnancy. CD4+ T cells from RUPP or normal pregnant (NP) rats were adoptively transferred into NP rats on gestational day 13. Mean arterial pressure (MAP) was analyzed on gestational day 19, and tissues were collected for endothelin-1 analysis. MAP increased in placental ischemic RUPP rats versus NP rats (124.1 ± 3 vs. 96.2 ± 3 mmHg; P = 0.0001) and increased in NP recipients of RUPP CD4+ T cells (117.8 ± 2 mmHg; P = 0.001 compared with NP). Adoptive transfer of RUPP CD4+ T cells increased placental preproendothelin-1 mRNA 2.1-fold compared with NP CD4+ T cell rats and 1.7-fold compared with NP. Endothelin-1 secretion from endothelial cells exposed to NP rat serum was 52.2 ± 1.9 pg·mg−1·ml−1, 77.5 ± 4.3 pg·mg−1·ml−1 with RUPP rat serum ( P = 0.0003); 47.2 ± .16 pg·mg−1·ml−1 with NP+NP CD4+ T cell serum, and 62.2 ± 2.1 pg·mg−1·ml−1 with NP+RUPP CD4+ T cell serum ( P = 0.002). To test the role of endothelin-1 in RUPP CD4+ T cell-induced hypertension, pregnant rats were treated with an endothelin A (ETA) receptor antagonist (ABT-627, 5 mg/kg) via drinking water. MAP was 92 ± 2 mmHg in NP+ETA blockade and 108 ± 3 mmHg in RUPP+ETA blockade; 95 ± 5 mmHg in NP+NP CD4+ T cells+ETA blockade and 102 ± 2 mmHg in NP+RUPP CD4+ T cells+ETA blockade. These data indicate the importance of endothelin-1 activation to cause hypertension via chronic exposure to activated CD4+ T cells in response to placental ischemia.

Impact of hyperleptinemia during placental ischemia-induced hypertension in pregnant rats

2021 ◽  
Author(s):  
Ana C. Palei ◽  
Hunter L. Martin ◽  
Barbara A. Wilson ◽  
Christopher D. Anderson ◽  
Joey P. Granger ◽  
...  
Keyword(s):  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
No Donor ◽  
Induced Hypertension ◽  
Cgmp Signaling ◽  
Uterine Perfusion ◽  
Plasma Leptin ◽  
Placental Ischemia

The prevalence of preeclampsia and obesity have increased. While obesity is a major risk factor for preeclampsia, the mechanisms linking these morbidities are poorly understood. Circulating leptin levels increase in proportion to fat mass. Infusion of this adipokine elicits hypertension in non-pregnant rats, but less is known about how hyperleptinemia impacts blood pressure during placental ischemia, an initiating event in the pathophysiology of hypertension in preeclampsia. We tested the hypothesis that hyperleptinemia during reduced uterine perfusion pressure (RUPP) exaggerates placental ischemia-induced hypertension. On gestational day (GD) 14, Sprague-Dawley rats were implanted with osmotic mini-pumps delivering recombinant rat leptin (1 mg/kg per min, i.v.) or vehicle concurrently with the RUPP procedure to induce placental ischemia or Sham. On GD 19, plasma leptin was elevated in Sham+Leptin and RUPP+Leptin. Leptin infusion did not significantly impact mean arterial pressure (MAP) in Sham. MAP was increased in RUPP+Vehicle vs. Sham+Vehicle. In contrast to our hypothesis, placental ischemia-induced hypertension was attenuated by leptin infusion. To examine potential mechanisms for attenuation of RUPP-induced hypertension during hyperleptinemia, endothelial-dependent vasorelaxation to acetylcholine was similar between Sham and RUPP; however, endothelial-independent vasorelaxation to the nitric oxide (NO)-donor, sodium nitroprusside, was increased in Sham and RUPP. These findings suggest that NO/cyclic guanosine monophosphate (cGMP) signaling was increased in the presence of hyperleptinemia. Plasma cGMP was elevated in Sham and RUPP hyperleptinemic groups compared to vehicle groups but plasma and vascular NO metabolites were reduced. These data suggest that hyperleptinemia during placental ischemia attenuates hypertension by compensatory increases in NO/cGMP signaling.

scholarly journals Blockade of CD40 ligand for intercellular communication reduces hypertension, placental oxidative stress, and AT1-AA in response to adoptive transfer of CD4+ T lymphocytes from RUPP rats

2015 ◽  
Vol 309 (10) ◽  
pp. R1243-R1250 ◽  
Author(s):  
Denise C. Cornelius ◽  
Javier Castillo ◽  
Justin Porter ◽  
Lorena M. Amaral ◽  
Nathan Campbell ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
T Cells ◽  
T Lymphocytes ◽  
Adoptive Transfer ◽  
Cell Communication ◽  
Cd40 Ligand ◽  
Type I ◽  
Uterine Perfusion ◽  
Placental Ischemia

Preeclampsia (PE) is associated with altered immune activation during pregnancy. We have previously shown that adoptive transfer of CD4+ T cells from the reduced uterine perfusion pressure (RUPP) rat model of PE increases blood pressure, oxidative stress (ROS), and inflammation in normal pregnant recipient rats. The objective of this study was to determine if blockade of communication via the CD40-CD40 ligand (CD40L) interaction between placental ischemia-induced CD4+ T cells with endogenous normal pregnant (NP) cells would improve pathophysiology that was previously observed in NP recipient rats of RUPP CD4+ T cells. Splenic CD4+ T lymphocytes were magnetically separated, incubated with 2.5 μg/ml anti-CD40 ligand (αCD40L) overnight, and transferred into NP rats on day 12 of gestation (NP+RUPP CD4+ T+anti-CD40L). On day 19 of gestation, blood pressure (MAP), blood, and tissues were collected. MAP was 99 ± 2 in NP ( n = 13), 116 ± 4 in NP+RUPP CD4+ T cells ( n = 7; P < 0.01); MAP only increased to 104 ± 2 in NP+RUPP CD4+ T cells+CD40L ( n = 24) ( P < 0.05 vs. NP+RUPP CD4+ T cells). Mechanisms of hypertension in response to RUPP CD4+ T cells include endothelin-1 (ET-1), ROS, and angiotensin II type I receptor (AT1-AA) were analyzed. Inhibition of CD40L binding reduced placental ET-1 to 2.3-fold above NP rats and normalized placental ROS from 318.6 ± 89 in NP+RUPP CD4+ T cells ( P < 0.05) to 118.7 ± 24 in NP+RUPP CD4+ T+anti-CD40L ( P < 0.05). AT1-AA was also normalized with inhibition of CD40L. These data suggest that placental ischemia-induced T-cell communication via the CD40L is one important mechanism leading to much of the pathophysiology of PE.

Abstract P225: Rupp Rat Model Cd4+ T Cells Activate Nk Cells And Cause Mitochondrial Oxidative Stress And Hypertension In Normal Pregnant Rats

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Evangeline M Deer ◽  
Kristin Reeve ◽  
Lorena M Amaral ◽  
Venkata Ramana Vaka ◽  
Michael Franks ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Rat Model ◽  
Adoptive Transfer ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Pregnant Rats ◽  
Atp Production

Preeclampsia (PE) is new onset hypertension during pregnancy and is associated with elevated inflammatory response such as CD4+ T cells, NK cells, and cytokines. We have previously shown women with PE exhibit increases in circulating and placental CD4+T cells and placental mitochondrial (mt) dysfunction/ROS compared to normal pregnant (NP) women. The Reduced Uterine Perfusion Pressure (RUPP) rat model produces many characteristics of PE such as hypertension, increases in CD4+ cells, increases in renal and placental NK cells, and mt dysfunction/ROS. We have previously demonstrated that RUPP CD4+T cells cause hypertension in NP rats, however the role of RUPP CD4+ T cells in stimulating NK cells to cause mt dysfunction/ROS are not elucidated. Therefore, we examined the effect of adoptive transfer of RUPP CD4+ T cells to activate NK cells in NP rats. Splenic CD4+ T cells were isolated from RUPP rats, cultured, and injected into NP rats on GD 13. On GD19, MAP values and blood/tissue samples were collected from both RUPP CD4+ T cell recipients and NP controls. Mitochondrial respiration and mtROS were measured in isolated mitochondria using the Oxygraph 2K and fluorescent microplate reader, respectively. A student’s t-test was used for statistical analysis. On GD19, MAP increased to 110±2 mmHg (n=13) in RUPP CD4+ T cell recipients compared to control NP rats 102±2 mmHg (n=7, p<0.05). Circulating cytolytic NK cells increased to 3±0.6% in RUPP CD4+ T cell recipients (n=8) compared to NP controls 0.3±0.2% (n=7, p<0.05). Placental state 3 (209.3±31.3 vs 422.7 ±83.3 pmol/sec/mg, p<0.05) and maximal (152.1±46.2 vs 229.7±58.9 pmol/sec/mg) and renal state 3 (133.4 ±21.4 vs 289.8±43.4 pmol/sec/mg, p<0.05) and maximal (61.8±18 vs 242.4±27.7 pmol/sec/mg, p<0.05) respiration rates, indicative of ATP production and electron transport chain efficacy respectively, were reduced with RUPP CD4+ T cells (n=6; n=9) compared to NP (n=5; n=5). Collectively, the data indicate that the adoptive transfer of RUPP CD4+ T cells stimulates cytolytic NK cells and placental and renal mitochondrial dysfunction/ROS during pregnancy as important mechanisms of hypertension in the pathophysiology of preeclampsia. Keywords: Preeclamspia, Hypertension, Oxidative stress

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 Activating autoantibodies to the angiotensin II type I receptor play an important role in mediating hypertension in response to adoptive transfer of CD4+ T lymphocytes from placental ischemic rats

2012 ◽  
Vol 302 (10) ◽  
pp. R1197-R1201 ◽  
Author(s):  
Sarah Richards Novotny ◽  
Kedra Wallace ◽  
Judith Heath ◽  
Janae Moseley ◽  
Pushpinder Dhillon ◽  
...  
Keyword(s):  
Blood Pressure ◽  
T Cells ◽  
T Cell ◽  
Angiotensin Ii ◽  
T Lymphocytes ◽  
B Cell ◽  
Inflammatory Cytokines ◽  
Adoptive Transfer ◽  
Type I ◽  
Placental Ischemia

Hypertension in rats with chronic placental ischemia (reduced uterine perfusion pressure, RUPP) is associated with elevated inflammatory cytokines, agonistic autoantibodies to the angiotensin II type I receptor (AT1-AA) and CD4+ T cells; all of which are elevated in preclamptic women. Additionally, we have shown that adoptive transfer of RUPP CD4+ T cells increases blood pressure, inflammatory cytokines, and sFlt-1. The objective of this study was to determine the long-term effects of RUPP CD4+ T cells on AT1-AA, renal and systemic hemodynamics in pregnant rats. To answer this question CD4+ T splenocytes were magnetically isolated on day 19 of gestation from control RUPP and normal pregnant (NP) rats and injected into a new group of NP rats at day 13 of gestation. On day 19 of gestation mean arterial pressure (MAP) and renal function (glomerular filtration rates, GFR) were analyzed and serum collected for AT1-AA analysis. To determine a role for AT1-AA to mediate RUPP CD4+ T cell-induced blood pressure increases, MAP was analyzed in a second group of rats treated with AT1 receptor blockade losartan (10 mg·kg−1·day−1) and in a third group of rats treated with rituximab, a B cell-depleting agent (250 mg/kg) we have shown previously to decrease AT1-AA production in RUPP rats. MAP increased from 101 ± 2 mmHg NP to 126 ± 2 mmHg in RUPP rats ( P < 0.001) and to 123 ± 1 mmHg in NP rats injected with RUPP CD4+ T cells (NP+RUPP CD4+T cells) ( P < 0.001). Furthermore, GFR decreased from 2.2 ml/min ( n = 7) in NP rats to 1.0 ml/min ( n = 5) NP+RUPP CD4+T cell. Circulating AT1-AA increased from 0.22 ± 0.1 units in NP rats to 13 ± 0.7 ( P < 0.001) units in NP+RUPP CD4+T cell-treated rats but decreased to 8.34 ± 1 beats/min in NP+RUPP CD4+ T cells chronically treated with rituximab. Hypertension in NP+RUPP CD4+T cell group was attenuated by losartan (102 ± 4 mmHg) and with B cell depletion (101 ± 5 mmHg). Therefore, we conclude that one mechanism of hypertension in response to CD4+ T lymphocytes activated during placental ischemia is via AT1 receptor activation, potentially via AT1-AA during pregnancy.

scholarly journals Characterization of Mitochondrial Bioenergetics in Preeclampsia

2021 ◽  
Vol 10 (21) ◽  
pp. 5063
Author(s):  
Ramana Vaka ◽  
Evangeline Deer ◽  
Mark Cunningham ◽  
Kristen M. McMaster ◽  
Kedra Wallace ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
T Cells ◽  
Cd4 T Cells ◽  
Type I ◽  
Pregnant Rats ◽  
Complex Iv ◽  
Tnf Α ◽  
Placental Ischemia

Preeclampsia (PE) is characterized by new onset hypertension during pregnancy and is associated with oxidative stress, placental ischemia, and autoantibodies to the angiotensin II type I receptor (AT1-AA). Mitochondrial (mt) dysfunction in PE and various sources of oxidative stress, such as monocytes, neutrophils, and CD4 + T cells, have been identified as important players in the pathophysiology of PE. We have established the significance of AT1-AA, TNF-α, and CD4 + T cells in causing mitochondrial (mt) dysfunction in renal and placental tissues in pregnant rats. Although the role of mt dysfunction from freshly isolated intact placental mitochondria has been compared in human PE and normally pregnant (NP) controls, variations among preterm PE or term PE have not been compared and mechanisms contributing to mt ROS during PE are unclear. Therefore, we hypothesized PE placentas would exhibit impaired placental mt function, which would be worse in preterm PE patients than in those of later gestational ages. Immediately after delivery, PE and NP patient’s placentas were collected, mt were isolated and mt respiration and ROS were measured. PE patients at either < or >34 weeks gestational age (GA) exhibited elevated blood pressure and decreased placental mt respiration rates (state 3 and maximal). Patients delivering at >34 weeks exhibited decreased Complex IV activity and expression. Placental mtROS was significantly reduced in both PE groups, compared to NP placental mitochondria. Collectively, the study demonstrates that PE mt dysfunction occurs in the placenta, with mtROS being lower than that seen in NP controls. These data indicate why antioxidants, as a potential target or new therapeutic agent, may not be ideal in treating the oxidative stress associated with PE.

scholarly journals T Cell‐Dependent B Cell Activation Mediates Pathophysiology in Reponse to CD4 + T Cells from Reduced Uterine Perfusion Pregnant Rats

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Denise Cornelius ◽  
Javier Castillo ◽  
Lorena Amaral ◽  
Kedra Wallace ◽  
Janae Moseley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
B Cell Activation ◽  
Pregnant Rats ◽  
Uterine Perfusion

scholarly journals Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction

2007 ◽  
Vol 204 (10) ◽  
pp. 2449-2460 ◽  
Author(s):  
Tomasz J. Guzik ◽  
Nyssa E. Hoch ◽  
Kathryn A. Brown ◽  
Louise A. McCann ◽  
Ayaz Rahman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Angiotensin Ii ◽  
Nadph Oxidase ◽  
Adoptive Transfer ◽  
Vascular Function ◽  
Type I ◽  
Perivascular Adipose Tissue

Hypertension promotes atherosclerosis and is a major source of morbidity and mortality. We show that mice lacking T and B cells (RAG-1−/− mice) have blunted hypertension and do not develop abnormalities of vascular function during angiotensin II infusion or desoxycorticosterone acetate (DOCA)–salt. Adoptive transfer of T, but not B, cells restored these abnormalities. Angiotensin II is known to stimulate reactive oxygen species production via the nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase in several cells, including some immune cells. Accordingly, adoptive transfer of T cells lacking the angiotensin type I receptor or a functional NADPH oxidase resulted in blunted angiotensin II–dependent hypertension and decreased aortic superoxide production. Angiotensin II increased T cell markers of activation and tissue homing in wild-type, but not NADPH oxidase–deficient, mice. Angiotensin II markedly increased T cells in the perivascular adipose tissue (periadventitial fat) and, to a lesser extent the adventitia. These cells expressed high levels of CC chemokine receptor 5 and were commonly double negative (CD3+CD4−CD8−). This infiltration was associated with an increase in intercellular adhesion molecule-1 and RANTES in the aorta. Hypertension also increased T lymphocyte production of tumor necrosis factor (TNF) α, and treatment with the TNFα antagonist etanercept prevented the hypertension and increase in vascular superoxide caused by angiotensin II. These studies identify a previously undefined role for T cells in the genesis of hypertension and support a role of inflammation in the basis of this prevalent disease. T cells might represent a novel therapeutic target for the treatment of high blood pressure.

scholarly journals Spontaneous Intestinal Tumorigenesis inApc/Min+Mice Requires Altered T Cell Development with IL-17A

2015 ◽  
Vol 2015 ◽  
pp. 1-11 ◽  
Author(s):  
Wook-Jin Chae ◽  
Alfred L. M. Bothwell
Keyword(s):  
T Cells ◽  
T Cell ◽  
Gene Mutation ◽  
Adoptive Transfer ◽  
Tumor Regression ◽  
T Cell Development ◽  
Cell Development ◽  
Intestinal Tumorigenesis

The control of inflammatory diseases requires functional regulatory T cells (Tregs) with significant Gata-3 expression. Here we address the inhibitory role of Tregs on intestinal tumorigenesis in theApc/Min+mouse model that resembles human familial adenomatous polyposis (FAP).Apc/Min+mice had a markedly increased frequency of Foxp3+ Tregs and yet decreased Gata-3 expression in the lamina propria. To address the role of heterozygousApcgene mutation in Tregs, we generatedFoxp3-Cre,Apcflox/+mice. Tregs from these mice effectively inhibited tumorigenesis comparable to wild type Tregs after adoptive transfer intoApc/Min+mice, demonstrating that the heterozygousApcgene mutation in Tregs does not induce the loss of control over tumor microenvironment. Adoptive transfer of in vitro generatedApc/Min+iTregs (inducible Tregs) failed to inhibit intestinal tumorigenesis, suggesting that naïve CD4 T cells generated fromApc/Min+mice thymus were impaired. We also showed that adoptively transferred IL-17A-deficientApc/Min+Tregs inhibited tumor growth, suggesting that IL-17A was critical to impair the tumor regression function ofApc/Min+Tregs. Taken together, our results suggest that both T cell development in a functional thymus and IL-17A control the ability of Treg to inhibit intestinal tumorigenesis inApc/Min+mice.

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