Elastin-Like Polypeptide: VEGF-B Fusion Protein for Treatment of Preeclampsia

Preeclampsia is characterized by the development of elevated blood pressure during the second and third trimesters of pregnancy that is accompanied by end organ dysfunction. The pathogenesis of preeclampsia is multifactorial but is commonly characterized by endothelial dysfunction and the overproduction of antiangiogenic factors, including the soluble VEGF (vascular endothelial growth factor) receptor sFlt-1 (soluble Fms-like tyrosine kinase receptor 1). Previously, administration of exogenous VEGF-A, bound to a carrier protein called ELP (elastin-like polypeptide), significantly reduced free sFlt-1 levels and attenuated the hypertensive response in a rodent model of preeclampsia. However, VEGF-A administration induces multifactorial effects mediated through its direct activation of the Flk-1 receptor. In response to this, we developed a therapeutic chimera using ELP bound to VEGF-B, a VEGF isoform that binds to sFlt-1 but not to Flk-1. The purpose of this study was to evaluate the in vitro activity and pharmacological properties of ELP-VEGF-B and to test its efficacy in the reduced uterine perfusion pressure rat model of placental ischemia. ELP-VEGF-B was less potent than ELP-VEGF-A in stimulation of endothelial cell proliferation and matrix invasion, indicating that it is a weaker angiogenic driver. However, after repeated subcutaneous administration in pregnant rats, ELP-VEGF-B was maternally sequestered and reduced blood pressure when compared with saline treated animals following induction of placental ischemia (123.38±11.4 versus 139.98±10.56 mm Hg, P =0.0129). Blood pressure reduction was associated with a restoration of the angiogenic capacity of plasma from rats treated with ELP-VEGF-B. ELP-VEGF-B is a nonangiogenic, maternally sequestered protein with potential efficacy for treatment of preeclampsia.

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Abstract 037: Exaggerated Placental Ischemia-induced Hypertension in Endothelin Receptor Type B (ETB)-deficient Pregnant Rats s Independent of Increased sFlt-1 or ROS Levels

Hypertension ◽

10.1161/hyp.70.suppl_1.037 ◽

2017 ◽

Vol 70 (suppl_1) ◽

Author(s):

Frank T Spradley

Keyword(s):

Blood Pressure ◽

Acute Hypoxia ◽

Pressure Control ◽

Normal Pregnancy ◽

Endothelin Receptor ◽

Maternal Circulation ◽

Pregnant Rats ◽

Uterine Perfusion ◽

Placental Ischemia ◽

In Pregnancy

While the pathogenesis of preeclampsia is not fully understood, studies implicate placental ischemia. Reduced uterine perfusion pressure (RUPP)-induced placental ischemia/hypoxia in animal models stimulates release of factors like antiangiogenic sFlt-1 into the maternal circulation increasing vascular-renal ET-1. ET-1 promotes hypertension via reactive oxygen species (ROS). Blockade of vasoconstrictive ETA abolishes RUPP hypertension. Deficiency of vasodilatory ETB in rats leads to increased blood pressure in pregnancy. While ETB deficiency markedly enhances RUPP hypertension, it is unknown if there is exaggerated RUPP-induced sFlt-1, ET-1 or ROS levels in ETB-def rats. The hypothesis was tested that placental ischemia/hypoxia-induced release of sFlt-1 and circulating ET-1 and ROS are greater in ETB-def rats. Eighteen-week-old ETB-def and transgenic (Tg) control pregnant rats were generated with Wistar Hannover males. RUPP or Sham surgeries were on gestational day 14 and assessment of plasmas and placentas at day 19. RUPP increased placental sFlt-1 (pg/mg) similarly in RUPP ETB-def (781±113, N=5) vs Sham ETB-def (573±54, N=12) and RUPP Tg (631±62, N=5) vs Sham Tg (547±31, N=12) (P<0.05). In placental explant cultures, acute hypoxia (48 h 1% O2 vs normoxia 6% O2) stimulated a comparable release of sFlt-1 (pg/mg) in Sham ETB-def (2577±135 vs 2070±78) and Sham Tg (3208±318 vs 2553±107) (P<0.05). Unexpectedly, plasma sFlt-1 (pg/mL) was lower in RUPP ETB-def (153±48) vs Sham ETB-def (476±125) and RUPP Tg (238±32) vs Sham Tg (463±102) (P<0.05). Plasma ET-1 (fmol/L) was exaggerated in RUPP ETB-def (954±70) and greater in Sham ETB-def (735±43) vs RUPP Tg (122±14) or Sham Tg (142±41) (P<0.05). Plasma H2O2 (umol/L) was not exaggerated in RUPP ETB-def (5.4±1.2) or RUPP Tg (4.0±0.5) but was greater (P<0.05) in Sham ETB-def (6.2±0.3) vs Sham Tg (3.6±0.3). In conclusion, these data suggest in 1) normal pregnancy, ETB is crucial for blood pressure control by regulating bioavailable ET-1 to prevent ROS production and 2) placental ischemia, ETB reduces excess ET-1 to buffer hypertension independently of sFlt-1 or ROS. These data support ETB physiology as important in controlling blood pressure in pregnancy and its loss in mediating hypertension in preeclampsia.

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

Hypertension ◽

10.1161/hypertensionaha.118.12028 ◽

2019 ◽

Vol 73 (1) ◽

pp. 162-170 ◽

Cited By ~ 3

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.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00724.2019 ◽

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.

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Abstract P320: Proliferationof Endogenous T-regs Improves the Pathophysiology Associated with Placental Ischemia of Pregnancy

Hypertension ◽

10.1161/hyp.68.suppl_1.p320 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Tarek Ibrahim ◽

Lukasz Przybyl ◽

Ashlyn C Harmon ◽

Denise C Connelius ◽

Mark W Cunningham ◽

...

Keyword(s):

Blood Pressure ◽

Inflammatory Cytokines ◽

Perfusion Pressure ◽

Treg Cells ◽

Proinflammatory Response ◽

Regulatory Interactions ◽

Uterine Perfusion ◽

Placental Ischemia ◽

Pro Inflammatory Cytokines ◽

New Onset

Preeclampsia (PE), new onset hypertension during pregnancy, is associated with pro-inflammatory cytokines and decreased regulatory immune mechanisms such as Tregs, IL-10 and IL-4. We believe this decrease in immune regulatory mechanisms leads to an uncontrolled proinflammatory response which contributes to most of the pathophysiology associated with PE. The Reduced Uterine Perfusion Pressure, RUPP, rat model of induced placental ischemia exhibits similar characteristics as women with PE including high blood pressure, elevated pro-inflammatory cytokines and cells and decreased Tregs, IL-4 and IL-10. Therefore, we hypothesized that stimulating Tregs by administration of a superagonist (SA) would increase the Treg profile in the RUPP rats which could reduce pro-inflammatory cytokines and blood pressure. The RUPP procedure was performed at gestation day 14 (GD14); SA was administered intraperitoneally at GD15, GD18 carotid catheters inserted, and GD19 MAP and pup weight, serum and tissues were collected. MAP in NP rats was 98.6 mmHg ± 4.71, 122.2 mmHg ± 1.84 in RUPPs which was improved to 110.789mmHg ± 1.23 in RUPP+SA. Circulating FoxP3+ Treg cells were 5.987% ± 1.69% of total T-cells population in NP, 0.77% ± 0.49% in RUPP rats but increased to 11.218% ± 2.9% in RUPP+SA; Circulating IL-6 levels were 41.008 ± 4.79 pg/mL in NP, 108.26 ± 25.99 pg/mL in RUPP, and 40.37 ± 4.49 pg/mL in RUPP+SA, Administration of the SA to the NP rats did not affect IL-6 Levels in comparison to NP at 36.79 ± 3.9 pg/mL. Plasma IL-10 Levels were at 58.399 ± 9.527 pg/mL in NP rats, these levels were significantly decreased in the RUPP rats, 26.298 ± 4.33 pg/mL, and treatment of the RUPPs with the SA significantly increased plasma IL-10 levels to 51.5486 ± 3.329 pg/mL. When the SA was given to NP rats, the levels for IL-10 were significantly higher compared to any of the other groups at 85.5207 ± 9.067 pg/mL. Placental Pre-pro Endothelin-1 (PPET-1) was increased 44.42 ± 0.269 fold in RUPP compared to NP 1 ± 0.255, but was decreased to 18.78 ± 0.48 in RUPP+SA. These data suggest an important role for up-regulating Treg cells to enhance the immune regulatory interactions and lower the hypertension without causing further reduction in fetal weight in response to placental ischemia during pregnancy.

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Interleukin-17 signaling mediates cytolytic natural killer cell activation in response to placental ischemia

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00285.2019 ◽

2020 ◽

Vol 318 (6) ◽

pp. R1036-R1046 ◽

Cited By ~ 1

Author(s):

Olivia K. Travis ◽

Dakota White ◽

Cedar Baik ◽

Chelsea Giachelli ◽

Willie Thompson ◽

...

Keyword(s):

Natural Killer ◽

Cell Activation ◽

Killer Cell ◽

Cytolytic Activity ◽

Interleukin 17 ◽

Inflammatory Protein ◽

Uterine Perfusion ◽

Nk Cytotoxicity ◽

Placental Ischemia

T-helper (TH)17s, IL-17, and cytolytic natural killer cells (cNKs) are increased in preeclampsia and contribute to the hypertension, inflammation, and fetal growth restriction that occurs in response to placental ischemia in the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. As IL-17 stimulates NK cytotoxicity in vitro, we tested the hypothesis that IL-17 inhibition in RUPP rats would decrease cNK activation as a mechanism to improve maternal and fetal outcomes. On gestation day (GD) 14, rats undergoing RUPP received a miniosmotic pump infusing IL-17RC (100 pg/day), a soluble IL-17 receptor (RUPP + IL-17RC). On GD19, mean arterial pressure (MAP) was measured in normal pregnant (NP), RUPP, and RUPP + IL-17RC rats ( n = 10–12/group), animals were euthanized, and blood and tissues were collected for analysis. MAP was 30% higher in RUPP compared with NP ( P < 0.0001) and was 12% lower in RUPP + IL-17RC ( P = 0.0007 vs. RUPP). Placental cytolytic NK cells were 132% higher in RUPP than in NP ( P = 0.04 vs. NP) and were normalized in RUPP + IL-17RC ( P = 0.03 vs. RUPP). Placental levels of TNF-α, a cNK-secreted cytokine, and macrophage inflammatory protein-3α (MIP-3α), a cNK chemokine, were higher in RUPP vs. NP and lower after IL-17 blockade. Placental VEGF was lower in RUPP vs. NP and was normalized in RUPP + IL-17RC. In vitro cytolytic activity of RUPP placental NKs was higher compared with NP and was blunted in RUPP + IL-17RC NKs. Finally, both fetal weight and placental weight were lower in RUPP compared with NP, and were improved in RUPP + IL-17RC. These data identify IL-17 as a mediator of cNK activation in response to placental ischemia during pregnancy.

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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

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00273.2015 ◽

2015 ◽

Vol 309 (10) ◽

pp. R1243-R1250 ◽

Cited By ~ 8

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.

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Abstract 037: A Role for IL-17 to Activate Cytolytic Natural Killer Cells in Response to Placental Ischemia

Hypertension ◽

10.1161/hyp.66.suppl_1.037 ◽

2015 ◽

Vol 66 (suppl_1) ◽

Author(s):

Denise C Cornelius ◽

D'Andrea S Thomas ◽

Jamil Elfarra ◽

Taia R McAfee ◽

Babbette LaMarca

Keyword(s):

Blood Pressure ◽

Nk Cells ◽

Renal Dysfunction ◽

Natural Killer ◽

Cell Activation ◽

Nk Cell ◽

Blood Pressure Response ◽

Cell Phenotype ◽

Uterine Perfusion ◽

Placental Ischemia

Women with preeclampsia (PE), newly developed hypertension and renal dysfunction during pregnancy, have small-for-gestational-age babies and demonstrate an increase in the inflammatory cytokine IL-17, placental oxidative stress, and cytolytic natural killer (NK) cell activation. The stimulus of the cytolytic NK cell phenotype during PE is currently unknown. Moreover, the specific role of cytolytic NK cells in the pathophysiology of preeclampsia has not been clearly defined. The reduced uterine perfusion pressure (RUPP) model of placental ischemia exhibits many of the characteristics of preeclampsia including hypertension, renal dysfunction, chronic inflammation and intrauterine growth restriction (IUGR). In this study, we tested the hypothesis that placental ischemia results in cytolytic activation of NK cells, and examined a role for the increased IL-17, in response to placental ischemia, to activate cytolytic NK cells. In this study, blood pressure (MAP) and pup weight were measured, and PBMCs and placental lymphocytes were examined via flow cytometry for surface makers of cytolytic NK cell activation. MAP significantly increased in response to placental ischemia from 103±4.1 mmHg in NP (n=6) to 129.1±3.1 mmHg (n=8) in RUPP rats (p<0.001). Neutralization of IL-17 with a soluble receptor attenuated the blood pressure response to 106.3±2.3 mmHg in RUPP+IL-17RC rats (n=3). Pup weight is significantly decreased in RUPP rats (2.52±0.18g in NP vs 2.03±0.05g in RUPP (p<0.05)), which increased to 2.54±0.36g in RUPP+IL-17RC. Cytolytic activation of circulating NK cells was not significantly changed among any of the groups (NP: 2.49±1.1%; RUPP: 7.74±3.2%; RUPP+IL-17RC:5.50±2.8%). However, cytolytic activation of placental NK cells increased in response to placental ischemia (NP: 3.4±1.1% vs RUPP 10.0±3.4%), and was completely attenuated after treatment with the soluble IL-17 receptor (RUPP+IL-17RC: 0.33±0.17%). These results suggest a role for placental ischemia and increased IL-17 to stimulate cytolytic NK cells. Furthermore, this study links the IL-17 pathway with cytolytic NK cell activation and IUGR in response to placental ischemia, potentially identifying new therapeutic targets to improve maternal and fetal outcomes of PE.

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Abstract P215: Hyperglycemic Rats Have Increased Fetal Demise But Not Hypertension During Pregnancy

Hypertension ◽

10.1161/hyp.76.suppl_1.p215 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Frank T Spradley ◽

Barbara Wilson ◽

Christopher Anderson

Keyword(s):

Blood Pressure ◽

Epidemiological Studies ◽

Adverse Outcomes ◽

Nitric Oxide Donor ◽

Gk Rat ◽

Pregnant Rats ◽

Fetal Demise ◽

Glucose Levels ◽

Maternal Hypertension ◽

Placental Ischemia

While obesity is a major cause for pregnancy complications including preeclampsia and fetal demise, it is not exactly clear the precise obesity-related metabolic factors that promote these adverse outcomes. Epidemiological studies have pointed toward hyperglycemia as one such factor. Therefore, we tested the hypothesis that hyperglycemic rats have hypertension and fetal demise during pregnancy. For this purpose, we utilized the type II diabetic model, the Goto-Kakizaki (GK) rat (N=16), compared to normoglycemic Wistar Hannover (WH) rats (N=9), which were maintained on Envigo 8640 standard chow. The GK rat allows for assessment of hyperglycemia on pregnancy without confounding obesity. Maternal fasting glucose levels were significantly greater (P<0.05) in GK (97±8 mg/dL) vs. WH (72±9 mg/dL) rats by gestational day 19. Body weight was lower (P<0.05) in GK (248±4 g) versus WH (289±4 g) pregnant rats, whereas perirenal fat (1.56±0.07 g vs. 1.38±0.07 g, P>0.05) and circulating levels of the adipokine, leptin (1.6±0.2 ng/mL vs. 2.2±0.3 ng/mL, P>0.05) were similar between GK and WH pregnant groups, respectively. Endothelial-dependent relaxation to acetylcholine (sensitivity as logEC50: -5.2±0.3 M vs -5.2±0.4 M) and endothelial-independent relaxation to the nitric oxide-donor sodium nitroprusside (logEC50: -7.2±0.2 M vs. -7.5±0.1 M) were similar (P>0.05) in uterine arteries isolated from GK and WH rats, respectively. It was then determined if reduced uterine perfusion pressure (RUPP)-induced placental ischemia, a significant contributor to the development of preeclampsia, promoted greater maternal hypertension in GK rats. RUPP was conducted on gestational day 14 and blood pressure assessed on day 19. RUPP produced hypertension to a similar extent (P>0.05) in GK (116±5 mmHg vs. Sham 102±5 mmHg) and WH (124±4 mmHg vs. Sham 100±2 mmHg) groups. Blood pressure was similar under Sham conditions. Fetal demise was already greater in Sham GK vs. Sham WH pregnant rats (% absorptions: 13±2 vs. 2±2, P<0.05) but increased similarly following RUPP in GK (61±11 %) and WH (65±5 %) pregnant rats. In conclusion, these data suggest that high glucose levels promote fetal demise during pregnancy but do not exaggerate the outcomes of placental ischemia-induced hypertension.

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Altered vascular contractility in adult female rats with hypertension programmed by prenatal glucocorticoid exposure

Journal of Endocrinology ◽

10.1677/joe.1.06506 ◽

2006 ◽

Vol 188 (3) ◽

pp. 435-442 ◽

Cited By ~ 31

Author(s):

P W F Hadoke ◽

R S Lindsay ◽

J R Seckl ◽

B R Walker ◽

C J Kenyon

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Adult Female ◽

Vascular Function ◽

Mesenteric Arteries ◽

Female Rats ◽

Control Group ◽

Pregnant Rats ◽

Vascular Contractility

Excessive exposure to glucocorticoids during gestation reduces birth weight and induces permanent hypertension in adulthood. The mechanisms underlying this programmed elevation of blood pressure have not been established. We hypothesised that prenatal glucocorticoid exposure may lead to vascular dysfunction in adulthood. Pregnant rats received dexamethasone (Dex) (100 μg/kg, s.c.) or vehicle (control) daily throughout pregnancy. Blood pressure was elevated (students t-test, unpaired; P < 0.05) in adult female offspring (aged 12–16 weeks) of Dex-treated mothers (148.0 ± 3.6 mmHg, n=10) compared with the control group (138.0 ± 2.5 mmHg, n=8). Vascular responsiveness in aortae and mesenteric arteries was differentially affected by prenatal Dex: aortae were less responsive to angiotensin II, whereas mesenteric arteries were more responsive to norepinephrine, vasopressin and potassium (mesenteric arteries respond poorly to angiotensin II in vitro). Acetylcholine-mediated, endothelium-dependent relaxation was similar in both groups. Prenatal exposure to Dex had no effect on blood pressure or aldosterone response to acute (15 min, i.v.) infusion of angiotensin II (75 ng/kg per min). In contrast, chronic (2-week, s.c.) infusion of angiotensin II (100 ng/kg per min) produced a greater elevation (P < 0.05) of blood pressure in Dex-treated rats (150.0 ± 3.6 mmHg) than in controls (135.3 ± 5.4 mmHg), and aldosterone levels were higher in Dex-treated animals. There was no angiotensin II-induced medial hypertrophy/hyperplasia in mesenteric arteries from Dex-treated rats. These results indicate that vascular function is altered in a region-specific manner in rats with glucocorticoid-programmed hypertension. Despite a striking increase in mesenteric artery contraction in Dex-treated rats, in vivo studies suggest that abnormalities of the renin-angiotensin-aldosterone system, rather than enhanced vascular contractility, may be responsible for the elevation of blood pressure in these animals.

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Placental Protein 13 Administration to Pregnant Rats Lowers Blood Pressure and Augments Fetal Growth and Venous Remodeling

Fetal Diagnosis and Therapy ◽

10.1159/000381914 ◽

2015 ◽

Vol 39 (1) ◽

pp. 56-63 ◽

Cited By ~ 10

Author(s):

Sveinbjorn Gizurarson ◽

Elisabet Run Sigurdardottir ◽

Hamutal Meiri ◽

Berthold Huppertz ◽

Marei Sammar ◽

...

Keyword(s):

Blood Pressure ◽

Spontaneous Mutation ◽

Blood Pressure Reduction ◽

Subsequent Development ◽

First Trimester ◽

Hypotensive Effect ◽

Carbohydrate Binding ◽

Pregnant Rats ◽

Beneficial Effects ◽

Placental Protein

Reduced first-trimester concentrations of placental protein 13 (PP13) are associated with subsequent development of preeclampsia, a major pregnancy disorder. We previously showed that PP13 has a vasodilatory effect, reduces blood pressure and augments expansive remodeling of the uteroplacental vasculature in pregnant rats. In this study, slow-release osmotic pumps were implanted in gravid rats (on day 8) to provide 1 week of PP13 supplementation. Treatment was associated with a reversible blood pressure reduction that returned to normal on day 15. In addition, PP13 caused venous expansion that is larger in the venous branches closer to the placenta. Then, it increased placental and pup weights. Similar administration of a truncated PP13 variant (DelT221) that is unable to bind carbohydrates (a rare spontaneous mutation associated with a high frequency of severe early preeclampsia among Blacks in South Africa) produced a hypotensive effect similar to the full-length molecule, but without venous remodeling and increased placental and pup weights. These results indicate the importance of PP13 carbohydrate binding for inducing vascular remodeling and improving reproductive outcome. Future studies are needed to determine whether beneficial effects would be evident in animal models of preeclampsia or in women predisposed to the development of preeclampsia.

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