Ana C. Palei

Pathophysiology of hypertension in pre-eclampsia: a lesson in integrative physiology

Despite being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for the pathogenesis of pre‐eclampsia have yet to be fully elucidated. However, it is evident that this is a complex disorder involving multiple organ systems, and by using integrative approaches, enormous progress has been made towards understanding the pathophysiology of pre‐eclampsia. Growing evidence supports the concept that the placenta plays a central role in the pathogenesis of pre‐eclampsia and that reduced uteroplacental perfusion, which develops as a result of abnormal cytotrophoblast invasion of spiral arterioles, triggers the cascade of events leading to the maternal disorder. Placental ischaemia leads to release of soluble placental factors, many of which are classified as anti‐angiogenic or pro‐inflammatory. Once these ischaemic placental factors reach the maternal circulation, they cause widespread activation and dysfunction of the maternal vascular endothelium that results in enhanced formation of endothelin‐1 and superoxide, increased vascular sensitivity to angiotensin II and decreased formation of vasodilators such as nitric oxide. This review highlights these links between placental ischaemia, maternal endothelial activation and renal dysfunction in the pathogenesis of hypertension in pre‐eclampsia.

Recent advances in the understanding of the pathophysiology of preeclampsia.

Preeclampsia, a pregnancy specific disorder, is typically defined as new-onset hypertension presenting after the 20th week of gestation with proteinuria. The overall prevalence in the United States is 3% to 8% with higher incidence in specific ethnic subpopulations, notably blacks. Preeclampsia is a major source of maternal and neonatal morbidity and mortality. Moreover, women who endure preeclampsia are at greater risk of cardiovascular diseases later in life. Studies published in Hypertension and other journals during the last few years have provided new insights not only into potential mechanisms underlying the pathophysiology of preeclampsia but also into the identification of potential biomarkers for the early diagnosis of preeclampsia. Although numerous factors have been implicated in the pathophysiology of preeclampsia, the main focus of this Recent Advances article is to review recent studies that link placental ischemia, endothelial and vascular dysfunction, and hypertension in preeclampsia. Despite intense research into the identification of molecular markers of preeclampsia, a reliable and accurate marker for the early diagnosis of preeclampsia remains elusive. A number of recent articles have suggested markers that could prove useful in the diagnosis of the disorder. With the growing interest in autoimmunity in preeclampsia, several studies have looked at immune factors in the maternal circulation as possible biomarkers. For instance, Siddiqui et al1 found widespread (≈95%) presence of agonistic autoantibodies to the angiotensin type-1 receptor (AT1-AA). Additionally, the levels of these autoantibodies correlated well with the degree of disease severity, suggesting potential use in diagnosis. In a related study, Jensen et al2 found that CD19(+)CD5(+) B-cell populations, a potential source for the AT1-AA, are significantly elevated in the maternal circulation of patients with preeclampsia during late gestation when compared with normal-pregnant controls at the same gestational stage. One of the most active areas of research in preeclampsia is angiogenic …

Sildenafil attenuates placental ischemia-induced hypertension

Preeclampsia is a complication of pregnancy that is marked by hypertension, proteinuria, and maternal endothelial dysfunction. A central factor in the etiology of the disease is the development of placental hypoxia/ischemia, which releases pathogenic soluble factors. There is currently no effective treatment for preeclampsia, but the phosphodiesterase-5 (PDE-5) inhibitor sildenafil has been suggested, as PDE-5 is enriched in the uterus, and its antagonism could improve uteroplacental function. Here, we report in the reduced uterine perfusion pressure (RUPP) rat model that administration of oral sildenafil is effective in attenuating placental ischemia-induced hypertension during gestation. RUPP animals have significantly elevated arterial pressure compared with control animals (132 ± 3 vs. 100 ± 2 mmHg; P < 0.05). Administration of oral sildenafil (45 mg·kg⁻¹·day⁻¹) had no effect on blood pressure in control rats but decreased pressure in RUPP rats (115 ± 1 mmHg; P < 0.05). RUPP induced changes in placental sFlt-1, and vascular endothelial growth factor (VEGF) was unaffected by sildenafil administration, as was the decrease in free plasma VEGF. RUPP animals had a significant increase in medullary PDE-5/β-actin ratio (1 ± 0.14 vs. 1.63 ± 0.18; P < 0.05) expression with a resulting reduction in renal medullary cGMP (1.5 ± 0.15 vs. 0.99 ± 0.1 pmol/μg protein, P < 0.05) compared with controls. Although sildenafil had no effect on renal medullary cGMP in control animals, it significantly increased cGMP in RUPP animals (1.3 ± 0.1 pmol/μg protein; P < 0.05). These data suggest that sildenafil might provide an effective therapeutic option for the management of hypertension during preeclampsia.

Immune Mechanisms Linking Obesity and Preeclampsia

Preeclampsia (PE) is characterized by hypertension occurring after the twentieth week of pregnancy. It is a significant contributor to maternal and perinatal morbidity and mortality in developing countries and its pervasiveness is increasing within developed countries including the USA. However, the mechanisms mediating the pathogenesis of this maternal disorder and its rising prevalence are far from clear. A major theory with strong experimental evidence is that placental ischemia, resulting from inappropriate remodeling and widening of the maternal spiral arteries, stimulates the release of soluble factors from the ischemic placenta causing maternal endothelial dysfunction and hypertension. Aberrant maternal immune responses and inflammation have been implicated in each of these stages in the cascade leading to PE. Regarding the increased prevalence of this disease, it is becoming increasingly evident from epidemiological data that obesity, which is a state of chronic inflammation in itself, increases the risk for PE. Although the specific mechanisms whereby obesity increases the rate of PE are unclear, there are strong candidates including activated macrophages and natural killer cells within the uterus and placenta and activation in the periphery of T helper cells producing cytokines including TNF-α, IL-6 and IL-17 and the anti-angiogenic factor sFlt-1 and B cells producing the agonistic autoantibodies to the angiotensin type 1 receptor (AT1-aa). This review will focus on the immune mechanisms that have been implicated in the pathogenesis of hypertension in PE with an emphasis on the potential importance of inflammatory factors in the increased risk of developing PE in obese pregnancies.

Increased risk for the development of preeclampsia in obese pregnancies: weighing in on the mechanisms

Preeclampsia (PE) is a pregnancy-specific disorder typically presenting as new-onset hypertension and proteinuria. While numerous epidemiological studies have demonstrated that obesity increases the risk of PE, the mechanisms have yet to be fully elucidated. Growing evidence from animal and human studies implicate placental ischemia in the etiology of this maternal syndrome. It is thought that placental ischemia is brought about by dysfunctional cytotrophoblast migration and invasion into the uterus and subsequent lack of spiral arteriole widening and placental perfusion. Placental ischemia/hypoxia stimulates the release of soluble placental factors into the maternal circulation where they cause endothelial dysfunction, particularly in the kidney, to elicit the clinical manifestations of PE. The most recognized of these factors are the anti-angiogenic sFlt-1 and pro-inflammatory TNF-α and AT1-AA, which promote endothelial dysfunction by reducing levels of the provasodilator nitric oxide and stimulating production of the potent vasoconstrictor endothelin-1 and reactive oxygen species. We hypothesize that obesity-related metabolic factors increase the risk for developing PE by impacting various stages in the pathogenesis of PE, namely, 1) cytotrophoblast migration and placental ischemia; 2) release of soluble placental factors into the maternal circulation; and 3) maternal endothelial and vascular dysfunction. This review will summarize the current experimental evidence supporting the concept that obesity and metabolic factors like lipids, insulin, glucose, and leptin affect placental function and increase the risk for developing hypertension in pregnancy by reducing placental perfusion; enhancing placental release of soluble factors; and by increasing the sensitivity of the maternal vasculature to placental ischemia-induced soluble factors.

Reduced uterine perfusion pressure induces hypertension in the pregnant mouse

Despite preeclampsia being one of the leading causes of maternal death and a major contributor of maternal and perinatal morbidity, the mechanisms responsible for its pathogenesis have yet to be fully elucidated. Growing evidence indicates that reduced uteroplacental perfusion and the resulting placental ischemia triggers the cascade of events leading to this maternal disorder. While the well-established rat model of reduced uterine perfusion pressure (RUPP) is providing invaluable insight into the etiology of preeclampsia, the aim of this study was to develop a mouse model of reduced uterine perfusion to expand mechanistic investigation by incorporation with novel gene-targeted mice. To accomplish this aim, a sham surgical procedure or a restriction of blood flow at the abdominal aorta and the ovarian arteries was initiated at day 13 of gestation in C57BL/6J mice. Mean arterial pressure measured in conscious, chronically instrumented mice was significantly elevated in the RUPP (120 ± 4 mmHg) compared with the sham (104 ± 4 mmHg) mice at day 18 of gestation (P < 0.01). Placental ischemia reduced fetal weights (0.95 ± 0.04 and 0.80 ± 0.02 g; RUPP vs. Sham, respectively; P < 0.02) and increased circulating levels of antiangiogenic soluble fms-related tyrosine kinases (sFlt)-1 (P < 0.05) in the RUPP at day 18 of gestation. Plasma concentrations of sFlt-1 are increased in preeclamptic patients and in response to reduced uterine perfusion in the rat. Thus, these results suggest that the mouse model of reduced uterine perfusion is applicable to facilitate novel mechanistic investigation into the etiology of hypertension that results from placental ischemia during pregnancy.

Obese melanocortin-4 receptor-deficient rats exhibit augmented angiogenic balance and vasorelaxation during pregnancy

While obesity is a major risk factor for preeclampsia, the mechanisms linking obesity and hypertension during preeclampsia remain unclear. Hypertension in preeclampsia is associated with placental ischemia‐induced release of antiangiogenic soluble fms‐like tyrosine kinase (sFlt‐1) into the maternal circulation, which antagonizes vascular endothelial growth factor (VEGF) promoting endothelial dysfunction. Haploinsufficiency, defined as loss of one copy of a gene via a mutation, of the melanocortin‐4 receptor (MC4R) is the most common cause of monogenetic obesity in humans. The purpose of our study was to determine the effects of genetic obesity on angiogenic balance, endothelial function, and blood pressure in pregnant MC4R+/− and MC4R+/+ rats. At gestational day (GD) 18, body weight and total body fat mass were greater in MC4R+/− than MC4R+/+ rats. On GD 19, plasma sFlt‐1 was not significantly different between groups. Interestingly, circulating VEGF was greater in the obese rats with the source being adipose tissue and not the placenta. Wire myography showed in third‐order mesenteric arteries that sensitivity (logEC50) to endothelial‐dependent and nitric oxide donor‐induced vasorelaxation was greater in MC4R+/− versus MC4R+/+. Mean arterial blood pressure was similar between groups. In conclusion, under normal pregnant conditions, genetically obese pregnant animals have greater angiogenic balance and dependency of vasorelaxation on nitric oxide signaling protecting against the development of hypertension. However, we speculate that, in the face of reduced uterine perfusion, a rise in circulating placental factors that target and reduce nitric oxide bioavailability exposes the susceptibility of genetically obese animals to greater hypertension in pregnancy.

Chronic hyperleptinemia results in the development of hypertension in pregnant rats

Despite the fact that obesity is a major risk factor for preeclampsia (PE), the pathophysiological mechanisms whereby obesity and metabolic factors such as leptin increase this risk are unclear. While human data have shown that hyperleptinemia is associated with PE, the long-term effect of hyperleptinemia on blood pressure during pregnancy is unknown. Thus we tested the hypothesis whether chronic circulating leptin elevations in pregnant rats increase blood pressure and placental factors known to play a role in PE. On gestational day (GD)14, rats were assigned to the normal pregnant group with food intake ad libitum (control), leptin-treated (0.5 μg·kg(-1)·min(-1) ip) pregnant group with food intake ad libitum (pregnant+LEP), and normal pregnant group with food intake adjusted to the food intake of pregnant+LEP rats (pregnant-FR). On GD19, mean arterial pressure (MAP) was assessed and tissues were collected. Serum leptin concentration was elevated in pregnant+LEP compared with control and pregnant-FR (18.0 ± 2.8 vs. 0.8 ± 0.1 vs. 0.3 ± 0.1 ng/ml; P < 0.05), which was associated with increased MAP (121.3 ± 8.1 vs. 102.4 ± 2.4 vs. 101.3 ± 1.8 mmHg; P < 0.05). Food intake and body weight were reduced in pregnant+LEP and pregnant-FR by the end of gestation. Additionally, placentas and fetuses of these groups were lighter than those of control. However, placental expression of tumor necrosis factor-α was significantly greater in pregnant+LEP compared with controls (1.6 ± 0.1 vs. 1.1 ± 0.1 pg/mg; P < 0.05). In conclusion, leptin increases blood pressure and placental tumor necrosis factor-α during pregnancy despite its effect of reducing food intake and body weight, and represents a mechanism whereby obesity can promote the development of hypertension in PE.

The heme oxygenases: important regulators of pregnancy and preeclampsia

The heme oxygenase system has long been believed to act largely as a housekeeping unit, converting prooxidant free heme from heme protein degradation into the benign bilirubin for conjugation and safe excretion. In recent decades, however, heme oxygenases have emerged as important regulators of cardiovascular function, largely through the production of their biologically active metabolites: carbon monoxide, bilirubin, and elemental iron. Even more recently, a number of separate lines of evidence have demonstrated an important role for the heme oxygenases in the establishment and maintenance of pregnancy. Early preclinical and clinical studies have associated defects in the heme oxygenase with the obstetrical complication preeclampsia, as well as failure to establish adequate placental blood flow, an underlying mechanism of the disorder. Several recent preclinical studies have suggested, however, that the heme oxygenase system could serve as a valuable therapeutic tool for the management of preeclampsia, which currently has few pharmacological options. This review will summarize the role of heme oxygenases in pregnancy and highlight their potential in advancing the management of patients with preeclampsia.

Role of Nitric Oxide Synthase on Blood Pressure Regulation and Vascular Function in Pregnant Rats on a High-Fat Diet

BACKGROUND While obesity is a leading risk factor for preeclampsia, the mechanisms whereby obese women are more susceptible to pregnancy-induced hypertension are unclear. As high-fat diet (HFD) is an important contributor to the development of obesity, we tested the hypothesis that pregnant rats on HFD have hypertension and endothelial dysfunction due to reduced nitric oxide synthase (NOS). METHODS Twelve-week-old Sprague-Dawley female rats were fed normal diet (ND, 13% fat kcal) or HFD (40% fat kcal) for 9 weeks. Timed-pregnant rats were then generated and the effect of HFD on mean arterial blood pressure (MAP) and vascular function was assessed on gestational day (GD) 19. RESULTS MAP was not different between HFD and ND pregnant rats. Intriguingly, sensitivity to acetylcholine-induced endothelium-dependent vasorelaxation was enhanced in small mesenteric arteries of HFD dams compared to ND controls (logEC50 -7.9 ± 0.3 vs. -6.7 ± 0.3 M; P < 0.05). Additionally, HFD dams exhibited higher mesenteric artery expression of NOS3 and plasma levels of NO metabolites than ND controls (1738.0 ± 316.4 vs. 1094.0 ± 82.5 pg/mg and 72.5 ± 8.7 vs. 39.7 ± 4.5 µM, respectively; both P < 0.05). Further, to determine the role of NOS in modulating blood pressure in HFD pregnant rats, animals were treated with the nonselective inhibitor Nω-Nitro-l-arginine methyl ester hydrochloride (100 mg/l, drinking water) from GD 14 to 19. It was found that NOS inhibition increased MAP equally in HFD and ND groups. CONCLUSIONS Contrary to our initial hypothesis, HFD dams were normotensive and presented increased endothelial function and NO/NOS3 levels. This enhanced NOS-mediated vascular function does not appear to have a major impact on blood pressure regulation of HFD-fed pregnant rats.