Prepregnancy obesity and sFlt1-induced preeclampsia in mice: developmental programming model of metabolic syndrome

Bytautiene, Egle; Tamayo, Esther; Kechichian, Talar; Drever, Nathan; Gamble, Phyllis; Hankins, Gary D.V.; Saade, George R.

doi:10.1016/j.ajog.2011.02.031

Cited by 23 publications

(18 citation statements)

References 39 publications

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“…Interestingly, signs of metabolic syndrome were also described in the offspring of mice with sFlt-1-induced PE and rats with surgically induced placental ischemia (44,45), supporting the notion that exposure to an adverse uterine environment during PE affects the long-term health of the offspring. Provocatively, the offspring of PE+PRAV mice were normotensive and did not show signs of metabolic disease like the offspring born to untreated PE mothers.…”

Section: Discussionmentioning

confidence: 57%

Pravastatin therapy during preeclampsia prevents long-term adverse health effects in mice

et al. 2018

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Section: Discussionmentioning

confidence: 57%

Pravastatin therapy during preeclampsia prevents long-term adverse health effects in mice

et al. 2018

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“…Indirect evidence to support that obesity exaggerates the deleterious effects of sFlt-1 on pregnancy was demonstrated by the finding that diet-induced obese pregnant mice infused with sFlt-1 have offspring that go on to develop the highest blood pressures when compared nonobese and noninfused controls (20).More direct data about the combined actions of sFlt-1 and obesity on maternal vascular function comes from studies showing that pro-angiogenic factors are important for vasorelaxation responses to hormones during healthy pregnancy. Indeed, treatment of rat and mouse small renal arteries with recombinant human relaxin significantly attenuated myogenic constriction, which was blocked by VEGF receptor antagonism, VEGF neutralizing antibodies, or NOS inhibition.…”

Section: Effects Of Obesity On Placental Ischemia-induced Endothelialmentioning

confidence: 93%

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

Spradley

Palei

Granger

2015

American Journal of Physiology-Regulatory, Integrative and Comp

114

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) 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-␣ 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. body mass index; inflammation; placental ischemia; pregnancy; RUPP; sFlt-1 PE IS A PREGNANCY-SPECIFIC DISORDER typically identified by new-onset hypertension in the second half of pregnancy. Although often accompanied by new-onset proteinuria, PE can be associated with many other signs and symptoms including headaches, visual disturbances, epigastric pain, and the development of edema (4,192). Globally, this disease affects over 8 million pregnancies per year and is estimated to account for 40 -60% of maternal deaths in developing countries (125). In the United States, there was a 25% increase in the rate of PE between the years 1987-2004 (189). This significant increase highlights the importance of understanding how risk factors like obesity play a role in the pathogenesis of this maternal syndrome. Obesity is defined as a body mass index (BMI) of greater than or equal to 30 kg/m 2 . Greater than one-half of pregnant women are overweight or obese (48), and more than two-thirds of reproductive-aged women in the United States are overweight or obese (49). Although mounting epidemiological evidence supports obesity as a major risk factor for PE, the mechanisms linking these two morbidities are...

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“…Importantly, reduction of the plasma level of sFlt-1 in women with preterm preeclampsia using dextran sulfate apheresis has been reported to reduce proteinuria and blood pressure and prolong pregnancy by 23 days without apparent adverse events for mother or fetus (Thadhani et al, 2011). Moreover, the injection of mice with adenovirus expressing sFlt-1 results in pathophysiological findings resembling preeclampsia (Maynard et al, 2003; Bytautiene et al, 2011; Murphy et al, 2012). This animal model has been employed to study not only the pathophysiology of preeclampsia but also vascular alterations in the offspring (Lu et al, 2007a; Byers et al, 2009; Bytautiene et al, 2011).…”

Section: Pathophysiology Of Preeclampsia: Current Hypothesesmentioning

confidence: 99%

“…Moreover, the injection of mice with adenovirus expressing sFlt-1 results in pathophysiological findings resembling preeclampsia (Maynard et al, 2003; Bytautiene et al, 2011; Murphy et al, 2012). This animal model has been employed to study not only the pathophysiology of preeclampsia but also vascular alterations in the offspring (Lu et al, 2007a; Byers et al, 2009; Bytautiene et al, 2011). …”

Section: Pathophysiology Of Preeclampsia: Current Hypothesesmentioning

confidence: 99%

“…For instance, reduced flow-mediated vasodilatation (a hallmark of endothelial dysfunction) has been reported in children born from preeclamptic pregnancies as compared to children born from normotensive pregnancies (Jayet et al, 2010; Lazdam et al, 2010; Kvehaugen et al, 2011; Davis et al, 2012b). In animal studies using mice, male offspring born from mothers with preeclamptic-like syndrome, generated by administration of adenovirus carrying sFlt-1, exhibited high blood pressure (Lu et al, 2007a,b) and increased vascular reactivity (Byers et al, 2009; Bytautiene et al, 2011) compared to controls.…”

Section: Endothelial Dysfunction and Impaired Angiogenesis In Offsprimentioning

confidence: 99%

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Impaired adenosine-mediated angiogenesis in preeclampsia: potential implications for fetal programming

et al. 2014

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Preeclampsia is a pregnancy-specific syndrome, defined by such clinical hallmarks as the onset of maternal hypertension and proteinuria after 20 weeks of gestation. The syndrome is also characterized by impaired blood flow through the utero-placental circulation and relative placental ischemia, which in turn, may generate feto-placental endothelial dysfunction. Endothelial dysfunction in offspring born from preeclamptic pregnancies has been associated with an increased risk of cardiovascular disease, including hypertension, later in life. Interestingly, diminished endothelial function, manifested by low angiogenic capacity, leads to hypertension in animal studies. Recently, we have shown that the adenosine receptor A2A/nitric oxide/vascular endothelial growth factor axis is reduced in human umbilical vein endothelial cells derived from preeclamptic pregnancies, an effect correlated with gestational age at onset of preeclampsia. We and others suggested that impaired vascular function might be associated with high cardiovascular risk in offspring exposed to pregnancy diseases. However, we are not aware of any studies that examine impaired adenosine-mediated angiogenesis as a possible link to hypertension in offspring born from preeclamptic pregnancies. In this review, we present evidence supporting the hypothesis that reduced adenosine-mediated angiogenesis during preeclamptic pregnancies might be associated with development of hypertension in the offspring.

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Prepregnancy obesity and sFlt1-induced preeclampsia in mice: developmental programming model of metabolic syndrome

Cited by 23 publications

References 39 publications

Pravastatin therapy during preeclampsia prevents long-term adverse health effects in mice

Pravastatin therapy during preeclampsia prevents long-term adverse health effects in mice

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

Impaired adenosine-mediated angiogenesis in preeclampsia: potential implications for fetal programming

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