Reduction In Uteroplacental Perfusion Research Articles

Preeclampsia: Narrative review for clinical use

AimPreeclampsia is a very complex multisystem disorder characterized by mild to severe hypertension. MethodsPubMed and the Cochrane Library were searched from January 1, 2002 to March 31, 2022, with the search terms “pre-eclampsia” and “hypertensive disorders in pregnancy”. We also look for guidelines from international societies and clinical specialty colleges and we focused on publications made after 2015. ResultsThe primary issue associated with this physiopathology is a reduction in utero-placental perfusion and ischemia. Preeclampsia has a multifactorial genesis, its focus in prevention consists of the identification of high and moderate-risk clinical factors. The clinical manifestations of preeclampsia vary from asymptomatic to fatal complications for both the fetus and the mother. In severe cases, the mother may present renal, neurological, hepatic, or vascular disease. The main prevention strategy is the use of aspirin at low doses, started from the beginning to the end of the second trimester and maintained until the end of pregnancy. ConclusionPreeclampsia is a multisystem disorder; we do not know how to predict it accurately. Acetylsalicylic acid at low doses to prevent a low percentage, especially in patients with far from term preeclampsia. There is evidence that exercising for at least 140 min per week reduces gestational hypertension and preeclampsia. Currently, the safest approach is the termination of pregnancy. It is necessary to improve the prediction and prevention of preeclampsia, in addition, better research is needed in the long-term postpartum follow-up.

The maternal reduced uteroplacental perfusion model of preeclampsia induces sexually dimorphic metabolic responses in rat offspring

BackgroundOffspring born to preeclamptic mothers are prone to obesity, diabetes and hypertension in later life, but still, studies investigating the underlying mechanism are limited. Here, we aimed to investigate the impact of the reduced uteroplacental perfusion (RUPP) rat preeclampsia model on offspring metabolic outcomes.MethodsTimed pregnant Wistar rats underwent RUPP or sham surgeries on day 14 of gestation. Glucometabolic parameters were evaluated on postnatal days (PND), 14 (childhood), and 60 (young adult). In addition, intraperitoneal glucose tolerance test (IPGTT), homeostatic model assessment of insulin resistance (HOMA-IR), immunohistochemical staining for insulin in pancreatic islets, arterial blood pressure and 24-h urine protein (24hUP) excretion were performed at PND60.ResultsMale, but not female, young adult rats (PND60) of RUPP dams exhibited an impaired IPGTT, decreased circulatory insulin and weakened pancreatic insulin immunoreactivity. Compared to the male offspring of the sham group, the body mass of male RUPP offspring significantly caught up after PND42, but it was not sex-specific. RUPP pups also exhibited upregulations in glucagon (only males) and ghrelin (both sexes with a more significant increase in males) during PND14–PND60. However, in sham offspring (both sexes), glucagon levels were downregulated and ghrelin levels unchanged during PND14–PND60. The blood pressure, HOMA-IR and 24hUP values did not alter in RUPP pups.ConclusionsThe overall results suggest that maternal RUPP has negative and sex-specific impacts on insulin, glucagon and ghrelin regulations in offspring and that, as young adults, male RUPP rats may be more prone to develop obesity and diabetes.

Role of Macrophages in Developmental Programming of Pancreatic β‐Cell Area in Offspring of Gestational Hypertension

Preeclampsia is a pregnancy specific complication characterized by new‐onset maternal hypertension and a high incidence of intrauterine growth restriction (IUGR), both associated with negative outcomes for offspring. Our previous studies indicated that IUGR in conjunction with maternal hypertension in the rat Reduced Uteroplacental Perfusion Pressure (RUPP) model of chronic placental ischemia results in female offspring with reduced pancreatic β‐cell area compared to sham pregnancies at embryonic day 19, and this decrease in β‐cell area persists to postnatal day 13 (PD13). Pancreatic β‐cell area, set very early in life, can influence whether an individual develops type 2 diabetes (T2D). Consistent with reduced β‐cell area, previous studies of others have demonstrated oral glucose intolerance in 6‐12 month RUPP offspring. T2D is associated with increased macrophages in the pancreas, and we previously reported increased message for macrophage marker CD68 is associated with reduced β‐cell area in islets of female PD13 RUPP animals. Thus, we hypothesized that macrophages are crucial to the reduction in β‐cell area in RUPP offspring. To test this hypothesis, we determined if postnatal depletion of macrophages rescued the β‐cell area. Chronic placental ischemia was induced in timed‐pregnant Sprague‐Dawley rats using the RUPP model by surgical placement of clips on abdominal aorta and uterine arteries on gestation day 14 of a 21‐day gestation. Female offspring were intraperitoneally injected with control liposomes or clodronate liposomes (56 and 28 mg clodronate/kg on PD2 and PD9, respectively) to deplete macrophages. On PD13, offspring were euthanized and pancreata fixed in formalin for paraffin embedding and determination of β‐cell area. Other pancreata were perfused with collagenase and digested for islet isolation by hand‐picking. β‐cell/pancreas area was determined by immunofluorescence and image analysis. Female RUPP animals treated with control liposomes had significantly reduced β‐cell area compared to sham offspring treated with control liposomes (0.0156 vs 0.0242 β‐cell/pancreas area, n=5, p<0.05). Notably, β‐cell area of sham or RUPP offspring treated with clodronate liposomes was not different (0.0221 vs 0.0225 β‐cell/pancreas area, n= 6‐7) from sham animals treated with control liposomes (0.0242 β‐cell/pancreas area, n=5). Thus, clodronate liposome treatment rescued the defect in β‐cell area of female RUPP offspring compared to RUPP animals treated with control liposomes. Message for CD68 in islets was significantly decreased following clodronate treatment, suggesting depletion in the islet. In addition, macrophages were significantly depleted in peritoneal lavage, spleen and islets as determined by flow cytometry. Total macrophages in lavage decreased from 7.1 x 10^5 to 0.05 x 10^5 cells following clodronate treatment. Thus, our studies suggest macrophages are critical for the reduction in β‐cell area in RUPP offspring following chronic placental ischemia. Future studies will explore the influence of apoptosis, proliferation, β‐cell size and number on reduction in β‐cell area.

Hypertension in Pregnancy: Diagnosis, Blood Pressure Goals, and Pharmacotherapy: A Scientific Statement From the American Heart Association.

Hypertensive disorders of pregnancy (HDP) remain one of the major causes of pregnancy-related maternal and fetal morbidity and mortality worldwide. Affected women are also at increased risk for cardiovascular disease later in life, independently of traditional cardiovascular disease risks. Despite the immediate and long-term cardiovascular disease risks, recommendations for diagnosis and treatment of HDP in the United States have changed little, if at all, over past decades, unlike hypertension guidelines for the general population. The reasons for this approach include the question of benefit from normalization of blood pressure treatment for pregnant women, coupled with theoretical concerns for fetal well-being from a reduction in utero-placental perfusion and in utero exposure to antihypertensive medication. This report is based on a review of current literature and includes normal physiological changes in pregnancy that may affect clinical presentation of HDP; HDP epidemiology and the immediate and long-term sequelae of HDP; the pathophysiology of preeclampsia, an HDP commonly associated with proteinuria and increasingly recognized as a heterogeneous disease with different clinical phenotypes and likely distinct pathological mechanisms; a critical overview of current national and international HDP guidelines; emerging evidence that reducing blood pressure treatment goals in pregnancy may reduce maternal severe hypertension without increasing the risk of pregnancy loss, high-level neonatal care, or overall maternal complications; and the increasingly recognized morbidity associated with postpartum hypertension/preeclampsia. Finally, we discuss the future of research in the field and the pressing need to study socioeconomic and biological factors that may contribute to racial and ethnic maternal health care disparities.

Decreased Systemic Complement Activation Product C3a is Associated with a Reduction in Pancreatic β Cell Area in Islets of Female Rat Offspring following Chronic Placental Ischemia‐induced Hypertension

Preeclampsia is a pregnancy specific condition characterized by new-onset maternal hypertension and increased systemic inflammation, including increased complement activation. Our previous studies demonstrated that inhibition of complement activation attenuated placental ischemia-induced hypertension in the Reduced Uteroplacental Perfusion Pressure (RUPP) model of gestational hypertension in rat. Hypertensive pregnancy disorders can also result in increased risk of later-life cardiovascular and metabolic disease for the offspring. In fact, recent studies have demonstrated that gestational hypertension is associated with increased risk for Type 2 diabetes in offspring. Clearly, pancreatic β cell mass, established early in life, can influence whether an individual develops Type 2 diabetes. β cell area has also been linked to complement component C3 and activation product C3a, with increased C3a generation associated with prevention of human islet cell atrophy. Our previous studies demonstrated a significant reduction in β cell area in postnatal day (PD)13 female, but not male, offspring of rats subjected to chronic placental ischemia-induced hypertension in the RUPP model. Thus, we hypothesized that decreased C3a is associated with reductions in β cell area in the female offspring following placental insufficiency. The RUPP model was used to induce placental insufficiency by placing silver clips on the abdominal aorta and uterine arteries on gestation day 14 of a 21 day gestation. Serum was collected via the abdominal aorta from PD13 pups born from RUPP and Sham pregnancies. Pancreatic islets of PD13 male and female offspring of RUPP and Sham dams were isolated by collagenase perfusion and handpicking. We previously demonstrated that the transcript message for membrane-bound complement regulator CD55 (negative regulator of C3 activation) was significantly increased in islets isolated from female, but not male, RUPP vs Sham offspring, with no change in acinar tissue. In addition, no significant change was observed in message for the parent molecule C3. The relative amount of circulating C3a in serum of PD13 offspring was determined by Western blot and expressed as C3a units/ul based on signal intensity of 1 ul of a standard pool of adult rat serum activated by yeast. Circulating C3a in female RUPP offspring (1.35 ± 0.37 units/ul) was significantly lower (p<0.05) than C3a in female Sham offspring (2.54 ± 0.44 units/ul). No difference was noted comparing C3a in serum of male offspring, RUPP vs Sham, where no change in β cell area has been observed. Thus, these data suggest an increase in CD55 may limit complement activation and C3a production in female offspring. This dysregulation of complement activation may contribute to reduction of β cell area and long-term susceptibility for Type 2 diabetes. Future studies are needed to determine if local or circulating C3a is instrumental in controlling pancreatic β cell area in offspring of hypertensive pregnancies.

Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model

An imbalance in angiogenic growth factors and poor utero-placental perfusion are strongly associated with preeclampsia. The reduced utero-placental perfusion (RUPP) model that mimics insufficient placental perfusion is used to study preeclampsia. The aim of this study was to develop a refined RUPP model in C57Bl/6 J mice to test the efficacy of MZe786 as a potential inhibitor of soluble Flt-1 for preeclampsia therapy. Murine RUPP (mRUPP) was induced through bilateral ligation of the ovarian arteries at E11.5 that resulted in typical preeclampsia symptoms including increase in mean arterial pressure (MAP), kidney injury and elevated soluble Flt-1 (sFlt-1) levels in the maternal plasma and amniotic fluid. The murine RUPP kidneys showed tubular and glomerular damage along with increased oxidative stress characterised by increased nitrotyrosine staining. The mRUPP displayed abnormal placental vascular histology, reduced expression of placental cystathionine γ-lyase (CSE), the hydrogen sulfide (H2S) producing enzyme, and resulted in adverse fetal outcomes (FGR). Importantly, oral administration of hydrogen sulfide (H2S)-releasing compound MZe786 from E11.5 to E17.5 successfully prevented the development of preeclampsia. Specifically, MZe786 treatment reduced maternal MAP and kidney nitrotyrosine staining and improved fetal outcome. The circulation levels of sFlt-1 were dramatically decreased in MZe786 treated animals implying that H2S released from MZe786 offered protection by inhibiting sFlt-1 levels. MZe786 prevent preeclampsia and warrant a rapid move to randomised control clinical trial.

Characterisation of the Selective Reduced Uteroplacental Perfusion (sRUPP) Model of Preeclampsia

Preeclampsia is a complication of pregnancy characterised by gestational hypertension, proteinuria and/or end organ disease. The reduced uteroplacental perfusion (RUPP) model, via partial occlusion of the lower abdominal aorta, mimics insufficient placental perfusion as a primary causal characteristic of preeclampsia. However, a major limitation of the RUPP model is that perfusion is reduced to the entire hindquarters of the rat resulting in hindlimb ischemia. We hypothesised that clipping the uterine and ovarian arteries in the selective (s)RUPP model would provoke signs of preeclampsia while avoiding systemic ischemia. Sham, RUPP or sRUPP procedures were performed in pregnant Sprague Dawley rats on gestational day (GD)14. On GD21 uterine blood flow was significantly reduced in both the RUPP and sRUPP models while aortic flow was reduced only in RUPP. Both models resulted in increased MAP, increased vascular oxidative stress (superoxide generation), increased pro-inflammatory (RANTES) and reduced pro-angiogenic (endoglin) mediators. Vascular compliance and constriction were unaltered in either RUPP or sRUPP groups. In summary, refinements to the RUPP model simultaneously maintain the characteristic phenotype of preeclampsia and avoid peripheral ischemia; providing a useful tool which may be used to increase our knowledge and bring us closer to a solution for women affected by preeclampsia.

365. Maternal and fetal consequences of preeclampsia

Vascular dysfunction in women with preeclampsia is complex. Placenta-derived circulating factors and/or the maternal response to these factors contribute to vascular endothelial cell dysfunction. Risk factors for preeclampsia include many conditions such as maternal aging, pre-existing hypertension, obesity and diabetes. The heterogeneity of this population, including the diversity of circulating factors such as oxLDL, TNF α , and advanced glycation end products, has contributed to the overall complexity of targeting a specific pathway for therapeutic prevention and/or intervention. Interestingly, these circulating factors are also among the factors known to upregulate and/or activate the lectin-like oxidized LDL receptor-1 (LOX-1). Our laboratory has shown that LOX-1 is increased in the systemic vasculature of women with preeclampsia and contributes to vascular oxidative stress. Moreover, our rat model of reduced uteroplacental perfusion (RUPP), which has preeclampsia-like signs, demonstrates increased LOX-1 expression, increased vascular oxidative stress and ultimately vascular dysfunction. Since LOX-1 has multiple ligands, it may be a point of convergence for many plasma factors known to be elevated in preeclampsia; including placental-derived microparticles; a current area of investigation. Notably, pregnancy has an important influence on both short- and long-term cardiovascular outcomes for women and their offspring. One risk factor for preeclampsia is maternal age, an important factor considering that the age at which women experience their first pregnancy has steadily increased through the decades. We use aged female rats (9.5 months; equivalent to ∼35 yr old human), to investigate the impact of maternal aging on later-life maternal and offspring cardiovascular health. Our data show that advanced maternal age worsens postpartum vascular function and that offspring born from aged dams have an altered cardiovascular risk profile that is sex-specific. These data further illustrate pregnancy as a window of opportunity to assess both maternal and offspring future cardiovascular risk.

Critical Imperative for the Reform of British Interpretation of Fetal Heart Rate Decelerations: Analysis of FIGO and NICE Guidelines, Post-Truth Foundations, Cognitive Fallacies, Myths and Occam's Razor.

Cardiotocography (CTG) has disappointingly failed to show good predictability for fetal acidemia or neonatal outcomes in several large studies. A complete rethink of CTG interpretation will not be out of place. Fetal heart rate (FHR) decelerations are the most common deviations, benign as well as manifestation of impending fetal hypoxemia/acidemia, much more commonly than FHR baseline or variability. Their specific nomenclature is important (center-stage) because it provides the basic concepts and framework on which the complex “pattern recognition” of CTG interpretation by clinicians depends. Unfortunately, the discrimination of FHR decelerations seems to be muddled since the British obstetrics adopted the concept of vast majority of FHR decelerations being “variable” (cord-compression). With proliferation of confusing waveform criteria, “atypical variables” became the commonest cause of suspicious/pathological CTG. However, National Institute for Health and Care Excellence (NICE) (2014) had to disband the “typical” and “atypical” terminology because of flawed classifying criteria. This analytical review makes a strong case that there are major and fundamental framing and confirmation fallacies (not just biases) in interpretation of FHR decelerations by NICE (2014) and International Federation of Gynecology and Obstetrics (FIGO) (2015), probably the biggest in modern medicine. This “post-truth” approach is incompatible with scientific practice. Moreover, it amounts to setting oneself for failure. The inertia to change could be best described as “backfire effect”. There is abundant evidence that head-compression (and other non-hypoxic mediators) causes rapid rather than shallow/gradual decelerations. Currently, the vast majority of decelerations are attributed to unproven cord compression underpinned by flawed disproven pathophysiological hypotheses. Their further discrimination based on abstract, random, trial and error criteria remains unresolved suggesting a false premise to begin with. This is not surprising considering that the commonest pathophysiology of intrapartum hypoxemia is contraction-induced reduction in uteroplacental perfusion (sometimes already compromised) and not cord compression at all. This distorted categorization causes confusion, false-alarm fatigue and difficulty in focusing on real pathological decelerations making CTG interpretation dysfunctional ultimately compromising patient safety. Obstetricians/midwives should demand reverting to the previous more scientific British categorization of decelerations based solely on time relationship to contractions as advocated by the pioneers like Hon and Caldeyro-Barcia, rather than accepting the current “post-truth” scenario.

Postpartum Vascular Dysfunction in the Reduced Uteroplacental Perfusion Model of Preeclampsia.

Preeclampsia is a disorder affecting 2–8% of all pregnancies, characterized by gestational hypertension (≥ 140/90 mmHg) and proteinuria (≥300 mg over 24 hours) diagnosed following the 20th week of pregnancy, and for which there is currently no available treatment. While the precise cause of preeclampsia is unknown, placental ischemia/hypoxia resulting from abnormal trophoblast invasion and maternal endothelial dysfunction are central characteristics. Preeclampsia is a major cause of both maternal and fetal morbidity and mortality in the perinatal period. In addition, women who have experienced preeclampsia are more likely to suffer cardiovascular disease later in life. The cause of this elevation in cardiovascular risk postpartum, however, is unknown. We hypothesize that there may be lasting vascular dysfunction following exposure to reduced uteroplacental perfusion during pregnancy that may contribute to increased cardiovascular risk postpartum. Using the rat reduced utero-placental perfusion pressure (RUPP) model of preeclampsia, blood pressure was assessed in dams at gestational day 20, one and three months postpartum. Mesenteric artery and aortic function were assessed using wire myography. We demonstrated hypertension and increased mesenteric artery responses to phenylephrine at gestational day 20, with the latter due to a decreased contribution of nitric oxide without any change in methylcholine-induced relaxation. At one month postpartum, we demonstrated a small but significant vasoconstrictive phenotype that was due to an underlying loss of basal nitric oxide contribution. At three months postpartum, endothelium-dependent relaxation of the aorta demonstrated sensitivity to oxLDL and mesenteric arteries demonstrated decreased nitric oxide bioavailability with impaired methylcholine-induced relaxation; indicative of an early development of endothelial dysfunction. In summary, we have demonstrated impaired vascular function following exposure to a RUPP pregnancy that continued into the postpartum period; suggesting that a pregnancy complicated by preeclampsia may predispose women to later life cardiovascular disease via ongoing vascular dysfunction.

Effects of Placental Ischemia Are Attenuated by 1,25-Dihydroxyvitamin D Treatment and Associated with Reduced Apoptosis and Increased Autophagy.

We evaluated the effects of administration of 1,25-dihydroxyvitamin D (1,25(OH)2D) during pregnancy on relieving adverse outcomes of preeclampsia and the pathologic and biochemical changes in reduction in uteroplacental perfusion (RUPP) model of rats. On day 1, 7, and 14 of pregnancy, rats in pregnant RUPP plus 1,25(OH)2D (RUPP+VD) group (n = 15) received 120 ng/100 g body weight/week of 1,25(OH)2D by subcutaneous injection, while rats in normal pregnant (n = 12) and the RUPP group (n = 14) received 1,25(OH)2D vehicle (saline solution). On day 19 of pregnancy, after measure of blood pressure and cardiac function and urine collection, rats were euthanized, and fetal and maternal serum, placenta, and heart and kidney were collected. Fetal mortality, urinary protein, glucose, and parameters for kidney function in serum were measured. We evaluated vitamin D receptor expression and pathological and ultrastructural changes in rat heart, kidney, and placenta. Levels of oxidative stress, endoplasmic reticulum (ER) stress, apoptosis, and autophagy were measured in placenta. Compared to RUPP rats, 1,25(OH)2D decreased fetal mortality, mean blood pressure, 24-h urinary protein, urine microalbumin, and hyperglycemia in RUPP+VD rats. These were consistent with the improvements of structure impairment in heart, kidney, and placenta of RUPP rat by 1,25(OH)2D. In placenta of RUPP rat, the decrease in oxidative stress and ER stress by 1,25(OH)2D treatment was accompanied by autophagy activation and apoptosis attenuation. 1,25(OH)2D plays a beneficial effect on preeclampsia at the early gestation and might be used as a potential protective agent for preeclampsia. However, the RUPP model only recapitulated the hypoxic origin of preeclampsia; further randomized controlled trial is expected to be performed for validation and evaluation.

Exercise Training Attenuates Placental Ischemia-Induced Hypertension and Angiogenic Imbalance in the Rat

An imbalance between proangiogenic (vascular endothelial growth factor) and antiangiogenic (soluble fms-like tyrosine kinase 1) factors plays an important role in hypertension associated with reduced uteroplacental perfusion (RUPP). Exercise has been shown to stimulate proangiogenic factors, such as vascular endothelial growth factor, in both the pregnant and nonpregnant state; thus, we hypothesized that exercise training would attenuate both angiogenic imbalance and hypertension attributed to RUPP. Four groups of animals were studied, RUPP and normal pregnant controls and normal pregnant and RUPP+exercise training. Exercise training attenuated RUPP-induced hypertension (P<0.05), decreased soluble fms-like tyrosine kinase 1 (P<0.05), increased VEGF (P<0.05), and elevated the soluble fms-like tyrosine kinase 1:vascular endothelial growth factor ratio. The positive effects of exercise on angiogenic balance in the RUPP rats were confirmed by restoration (P<0.05) of the RUPP-induced decrease in endothelial tube formation in human umbilical vascular endothelial cells treated with serum from each of the experimental groups. Placental prolyl hydroxylase 1 was increased (P<0.05) in RUPP+exercise training rats. Decreased trolox equivalent antioxidant capacity in the placenta, amniotic fluid, and kidney of the RUPP rats was reversed by exercise. RUPP-induced increase in renal thiobarbituric acid reactive species was attenuated by exercise. The present data show that exercise training before and during pregnancy attenuates placental ischemia-induced hypertension, angiogenic imbalance, and oxidative stress in the RUPP rat and reveals that increased prolyl hydroxylase 1 is associated with decreased soluble fms-like tyrosine kinase 1, thus revealing several potential pathways for exercise training to mitigate the effects of placental ischemia-induced hypertension. Lastly, the present study demonstrates that exercise training may be a useful approach to attenuate the development of placental ischemia-induced hypertension during pregnancy.

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

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 (ET(A)) receptor antagonist (ABT-627, 5 mg/kg) via drinking water. MAP was 92 ± 2 mmHg in NP+ET(A) blockade and 108 ± 3 mmHg in RUPP+ET(A) blockade; 95 ± 5 mmHg in NP+NP CD4(+) T cells+ET(A) blockade and 102 ± 2 mmHg in NP+RUPP CD4(+) T cells+ET(A) 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.

Lectin-Like Oxidized Low-Density Lipoprotein 1 Receptor in a Reduced Uteroplacental Perfusion Pressure Rat Model of Preeclampsia

Preeclampsia is a major cause of maternal and fetal morbidity and mortality that has been associated with endothelial dysfunction attributed, in part, to dyslipidemia, an imbalance in angiogenic factors and oxidative stress. One of the many factors that have been shown to be elevated in women with preeclampsia is low-density lipoprotein (LDL) and the more oxidizable, small dense LDL, which can lead to increased vascular oxidative stress and decreased bioavailability of NO. Lectin-like oxidized LDL-1 receptor (LOX-1) is a specific receptor for oxidized LDL. We hypothesized that a reduction of placental perfusion using a rat model of reduced uteroplacental perfusion pressure would result in enhanced LOX-1 expression in the maternal vasculature causing impaired vascular endothelial function through the actions of increased superoxide production and decreased NO-mediated vasodilation. We demonstrated a significant increase in the expression of the LOX-1 receptor (4.3-fold; P=0.002), endothelial NO synthase (2.7-fold; P=0.001), and superoxide (P=0.02) in thoracic aorta of the reduced uteroplacental perfusion pressure model, whereas maximal vasodilator function was modestly decreased (P<0.05). Endothelial-dependent vasodilator function was unaffected by either oxidized LDL or an LOX-1 receptor inhibitor in controls but was modestly increased in the presence of both oxidized LDL and the LOX-1 receptor inhibitor in reduced uteroplacental perfusion pressure (P=0.03). In summary, we have shown that, in a rat model of preeclampsia, there is a dramatic increase in the expression levels of both the LOX-1 receptor and the endothelial NO synthase enzyme, along with evidence of increased superoxide production and subsequent modestly decreased endothelial function.

Increased Myogenic Responses of Resistance-Sized Mesenteric Arteries After Reduced Uterine Perfusion Pressure in Pregnant Rats

Objective. A central component of preeclampsia is a reduction in utero-placental perfusion. We tested the hypothesis that vascular reactivity of second – order mesenteric arteries would be increased in a pregnant rat with reduced uterine perfusion pressure (RUPP). Methods. Pregnant 10–12 week old Sprague-Dawley rats underwent RUPP surgery on gestational day 14, and experiments were carried out on day 20. SHAM operated animals were used as controls. Resistance caliber mesenteric arteries (200–250 μm) were isolated, myogenic reactivity and responses to vasoconstrictor and vasodilator agonists were assessed utilizing a pressurized arteriograph system. Results. RUPP resulted in maternal hypertension and reductions in fetal number and weight. Resistance caliber mesenteric arteries (200–250 μm) were isolated, myogenic reactivity and responses to vasoconstrictor and vasodilator agonists were assessed utilizing a pressurized arteriograph system. Myogenic reactivity responses were normalized as a percent change in vessel diameter from an initial diameter at 20 mmHg. The mesenteric arteries from RUPP animals exhibited a significant increase in myogenic reactivity compared to SHAM controls (p < 0.05). This increased myogenicity was reversed with prostaglandin inhibition, suggesting a role for a vasoconstrictor prostaglandin. In addition to alterations in myogenic reactivity, resistance-sized arteries from RUPP animals have decreased responses to nitric oxide (NO) as evidenced by decreases in responses to methacholine (ME; P < 0.05) and no change in myogenic reactivity after NO synthase blockade. Conclusion. RUPP alters the behavior of resistance caliber arteries to favor a more contractile phenotype with decreased in NO responses, which is similar to what is seen in preeclampsia.

Chronic placental ischemia alters amniotic fluid milieu and results in impaired glucose tolerance, insulin resistance and hyperleptinemia in young rats

Although small size at birth is associated with hypertension and associated co-morbidities such as insulin resistance and type II diabetes mellitus, many of the animal models employed to simulate this phenomenon do not closely mimic the ontogeny of growth restriction observed clinically. While intrauterine growth restriction (IUGR) is often detected near mid-pregnancy in women and persists until term, most rodent models of IUGR employ ligation of uterine arteries for a brief period during late gestation (days 19-21 of pregnancy). We hypothesized that IUGR associated with chronic reduction in uteroplacental perfusion (RUPP) and placental ischemia during the third trimester of pregnancy in the rat alters the amniotic fluid (AF) environment and results in hypertensive offspring presenting with metabolic abnormalities such as glucose intolerance and insulin resistance. Insulin-like growth factor-1 (IGF-1), IGF-2, Na(+) concentration and oxidative stress in the AF were increased, while K(+) concentration was decreased in the RUPP compared with normal pregnant (NP) fetuses. RUPP-offspring (RUPP-O) were smaller (6.1 +/- 0.2 versus 6.7 +/- 0.2 g; P < 0.05) at birth compared with NP-offspring (NP-O) groups. At nine weeks of age, mean arterial pressure (121 +/- 3 versus 107 +/- 5 mmHg; P < 0.05), fasting insulin (0.71 +/- 0.014 versus 0.30 +/- 0.08 ng/mL; P < 0.05), glucose (4.4 +/- 0.2 versus 3.1 +/- 0.3 mmol/L; P < 0.05), leptin (3.8 +/- 0.5 versus 2.3 +/- 0.3 ng/mL; P < 0.05) and the homeostasis model assessment of insulin resistance index was greater (2.9 +/- 0.6 versus 1.0 +/- 0.3; P < 0.05) in the RUPP-O compared with the NP-O rats. These data indicate that chronic placental ischemia results in numerous alterations to the fetal environment that contributes to the development of impaired glucose metabolism, insulin resistance and hyperleptinemia in young offspring.

Hyperleptinemia and glucose intolerance in rat offspring with long‐term placental insufficiency

Placental insufficiency is a primary cause of intrauterine growth restriction (IUGR) in western societies and is associated with the development of chronic diseases such as hypertension and type 2 diabetes mellitus. We hypothesized that a chronic reduction in uteroplacental perfusion (RUPP) during the third trimester of pregnancy in the rat results in offspring with hypertension, insulin resistance and hyperleptinemia. IUGR was induced by placing silver clips on the abdominal aorta and ovarian arteries. At 9 weeks of age, arterial pressure (AP) was measured, blood samples collected and a glucose tolerance test performed in IUGR and normal pregnancy‐control offspring. AP was increased (121±3 vs. 107±5 mm Hg; P&lt;0.05) and birth weight was decreased (6.12±0.19 vs. 6.68±0.18g; P&lt;0.05) in IUGR compared to control rats. Fasting insulin (0.71±.014 vs. 0.30±0.08 ng/ml; P&lt;0.05), glucose (83 ± 7 vs. 54±4 mg/dl; P&lt;0.05), glucose clearance (area under curve; 26.8 ± 1.5 vs. 23.0 ± 0.8 mg*min/dL; P = 0.05) and leptin (3.8±0.5 vs. 2.3±0.3 ng/ml; P&lt;0.05) were increased in IUGR compared to control offspring. The homeostasis model assessment of insulin resistance index was greater in IUGR than control rats (2.9±0.6 vs. 1.0±0.3; P&lt;0.05). We conclude that chronic placental insufficiency during the third trimester results in development of hypertension, insulin resistance, and hyperleptinemia.

17-hydroxyprogesterone blunts the hypertensive response associated with reductions in uterine perfusion pressure in pregnant rats

Reduction in uteroplacental perfusion (RUPP) in pregnant rats is associated with hypertension, elevated cytokines, and activation of the endothelin (ET-1) system. Our objective was to determine whether the antiinflammatory properties of 17-alpha-hydroxyprogesterone caproate (17 OHP) reduce cytokine-stimulated vasoactive pathways that are associated with hypertension in response to placental ischemia. Mean arterial pressure (MAP), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, and renal ET-1 were measured in the following: pregnant controls, pregnant controls plus 17 OHP (6.6 mg/kg), RUPP rats, and RUPP rats plus 17 OHP. MAP increased 29 mm Hg in RUPP rats compared with pregnant controls (P < .001), whereas in RUPP plus 17 OHP rats, MAP increased only 19 mm Hg (P < .05). TNF-alpha and IL-6 increased 2- to 3-fold, respectively, in response to placental ischemia but was normalized in RUPP rats treated with 17 OHP. ET-1 increased 3-fold in RUPP rats but was markedly less in RUPP plus 17 OHP rats. 17 OHP blunts hypertension associated with RUPP, possibly via suppression of cytokine-stimulated ET-1 activation.

The Effects of Dietary Ascorbic Acid Treatment on Mesenteric Artery Reactivity in Pregnant Rats with Reduced Uterine Perfusion Pressure

Preeclampsia is a multifaceted disease of pregnancy mediated by poor placental perfusion. The symptoms of the disease include hypertension, hyperuricemia, and proteinuria. Pregnant rats with reduced uteroplacental perfusion (RUPP) have been used as an animal model of preeclampsia. In these animals plasma ascorbate levels are decreased along with increased vascular reactivity similar to what is seen in patients with preeclampsia. Therefore, the aim of this study was to determine the effects of dietary ascorbic acid (AA) treatment to animals with RUPP and to see if detrimental changes in mesenteric vascular reactivity seen in RUPP rats can be ameliorated. Sprague Dawley rats were subjected to RUPP or Sham surgery on Day 14 of gestation. Animals were then given regular water or ascorbic acid water (1 mg/mL) ad libitum post surgery. At gestational Day 21, resistance‐sized mesenteric arteries were harvested and mounted in a pressurized arteriograph. Myogenic reactivity was significantly decreased in AA treated RUPP animals compared to RUPP (p&lt;0.05). AA also reversed RUPP induced decreases in methacholine relaxation seen in RUPP (p&lt;0.05). These results suggest that antioxidant treatment can partially reverse the increased myogenic reactivity and decreased endothelium‐dependent relaxation seen in animals with reductions in uterine perfusion and may provide new insights into the treatment of human preeclampsia.

16: 17 OH progesterone blunts the hypertensive response associated with reductions in uterine perfusion pressure in pregnant rats

Reduction in uteroplacental perfusion (RUPP) is hypothesized to be the initiating factor for the development of hypertension during pregnancy. The objective of this study was to determine if 17OH Progesterone is a promising treatment for hypertension in response to placental ischemia in the pregnant rat. Arterial pressure (MAP) and endothelial factors were examined in a conscious, chronically instrumented rat model of RUPP with or without 17 OHP administration. Hypertension produced by RUPP is associated with endothelial dysfunction, enhanced ET-1 and ROS production, decreased NO synthesis, and a hypertensive shift in the pressure natriuresis relationship. Sprague-Dawley rats were anesthetized on Day 14 of pregnancy and underwent either 1) examination under anesthesia; 2) RUPP: the lower abdominal aorta was isolated and clipped (0.203mm ID) above the iliac bifurcation; branches of both the right and left ovarian arteries were clipped (0.100mm ID) 3) injection of intraperitoneal 17OHP, or 4) RUPP + injection of intraperitoneal 17OHP. On day 18, carotid artery catheters were placed in each rat; on day 19 MAP, maternal and pup weight were measured. Blood, kidneys and placentas were collected and weighed. MAP increased 23 mmHg in RUPP rats compared to control pregnant rats (126 +/−2 vs 103 +/−2 mmHg (p<0.03)). However, RUPP rats receiving progesterone displayed a 16 mmHg increase in MAP (119+/−2 (P0.03). ET-1 increased 3 fold in the cortex from RUPP rats (2.5 + 0.49 relative units, n=6) compared to normal pregnant rats(−1.5 + 0.9 relative units, n=6) (P<0.02) but was −0.6 relative units (n=4) in RUPP + 17 OHP. There was no change in maternal, pup or placental weights in response to 17 OHP administration in RUPP rats. Administration of 17 OH Progesterone blunts the hypertension associated with RUPP in pregnant rats possibly via protecting against endothelial activation that is associated with placental ischemia.