The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice

Lü, Fang; Longo, Monica; Tamayo, Esther; Maner, William L.; Al-Hendy, Ayman; Anderson, Garland D.; Hankins, Gary D.V.; Saade, George R.

doi:10.1016/j.ajog.2006.12.024

Cited by 195 publications

(163 citation statements)

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“…Studies using viral overexpression33, 57, 59, 60, 61 or direct infusion of sFlt‐132, 55, 62, 63 have demonstrated a critical role for this anti‐angiogenic factor for induction of hypertension and renal damage during pregnancy. Previous studies using exogenous VEGF infusion have reported reduced circulating sFlt‐1 levels 36, 64.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to Western blotting for total sFlt‐1 levels, we also assessed plasma sFlt‐1 by ELISA. The ELISA used has been previously reported to be specific for free, non‐VEGF‐bound, sFlt‐1 32, 53, 55, 56. We found that spiking the ELISA standard curves with ELP‐VEGF reduced the signal, suggesting that ELP‐VEGF might bind the Flt‐1 in the assay and prevent binding of 1 or both antibodies, thus confirming this as an assay for free sFlt‐1.…”

Section: Resultsmentioning

confidence: 99%

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A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

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Mahdi

Chapman

et al. 2017

JAHA

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BackgroundPreeclampsia is a hypertensive syndrome that complicates 3% to 5% of pregnancies in the United States. Preeclampsia originates from an improperly vascularized and ischemic placenta that releases factors that drive systemic pathophysiology. One of these factors, soluble fms‐like tyrosine kinase‐1, is believed to sequester vascular endothelial growth factor (VEGF), leading to systemic endothelial dysfunction and hypertension. With the goal of targeting soluble fms‐like tyrosine kinase‐1 while simultaneously preventing fetal exposure to VEGF, we fused VEGF to elastin‐like polypeptide, a biopolymer carrier that does not cross the placental barrier (ELP‐VEGF).Methods and Results ELP‐VEGF restored in vitro endothelial cell tube formation in the presence of plasma from placental ischemic rats. Long‐term administered ELP‐VEGF in pregnant rats accumulated in maternal kidneys, aorta, liver, and placenta, but the protein was undetectable in the pups when administered at therapeutic doses in dams. Long‐term administration of ELP‐VEGF in a placental ischemia rat model achieved dose‐dependent attenuation of hypertension, with blood pressure equal to sham controls at a dose of 5 mg/kg per day. ELP‐VEGF infusion increased total plasma soluble fms‐like tyrosine kinase‐1 levels but dramatically reduced free plasma soluble fms‐like tyrosine kinase‐1 and induced urinary excretion of nitrate/nitrite, indicating enhanced renal nitric oxide signaling. ELP‐VEGF at up to 5 mg/kg per day had no deleterious effect on maternal or fetal body weight. However, dose‐dependent adverse events were observed, including ascites production and neovascular tissue encapsulation around the minipump.Conclusions ELP‐VEGF has the potential to treat the preeclampsia maternal syndrome, but careful dosing and optimization of the delivery route are necessary.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

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Mahdi

Chapman

et al. 2017

JAHA

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“…18,19 These circulating proteins have been shown to have pathogenetic roles in hypertension in preeclampsia, 20 in human chronic kidney disease, 21 coronary artery disease 22 and in animal models of hypertension. 23,24 However, none of the studies have examined the relationship between endothelial dysfunction and hypertension in relationship to hypoxia exposure in OSA patients. Further, it is not known whether endothelial dysfunction is related to angiogenesis inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Endothelial dysfunction and hypertension in obstructive sleep apnea – Is it due to intermittent hypoxia?

Jafari

Mohsenin

2013

Journal of Cardiovascular Disease Research

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a b s t r a c tBackground: Obstructive sleep apnea (OSA) is a prevalent disorder causing hypertension. Endothelial dysfunction appears to underlie development of hypertension. It is not known whether hypoxia during sleep is necessarily the prerequisite process for endothelial dysfunction and hypertension in OSA. We therefore examined the relationship between endothelial-dependent vasodilatory capacity, hypoxia and circulating angiogenesis inhibitors in OSA. Methods and results:We studies 95 subjects with and without OSA and hypertension. Endothelialdependent vasodilation was assessed using brachial artery flow-mediated vasodilation method (FMD). Plasma angiogenesis inhibitors, endoglin (sEng) and fms-like tyrosine kinase-1 (sFlt-1), were measured using ELISA. The apneaehypopnea indexes were 41 AE 5 and 48 AE 4 events/hr in normotensive OSA (N-OSA) and hypertensive OSA (H-OSA), respectively, indicating severe OSA. The sleep time spent with SaO 2 < 90% (T < 90%) were 34 AE 8 and 40 AE 9 min, respectively. FMD was markedly impaired in H-OSA (8.0% AE 0.5) compared to N-OSA (13.5% AE 0.5, P < 0.0001), H-non-OSA (10.5% AE 0.8, P < 0.01), and N-non-OSA (16.1% AE 1.0, P < 0.0001). There was no correlation between T < 90% and FMD. Both OSA groups had elevated levels of sFlt-1 (62.4 AE 5.9 and 63.9 AE 4.7 pg/ml) compared to N-non-OSA (32.1 AE 6.5, P ¼ 0.0008 and P ¼ 0.0004, respectively) and H-non-OSA (41.2 AE 7.0, P < 0.05 and P ¼ 0.03, respectively). In contrast, sEng was only elevated in H-OSA (4.20 AE 0.17 ng/ml) compared with N-OSA (3.64 AE 0.14, P ¼ 0.01) and N-non-OSA (3.48 AE 0.20, P ¼ 0.01). There was a modest but statistically significant inverse correlation between sEng and FMD in only H-OSA group (r ¼ À0.38, P < 0.05). Conclusion: These data show that patients with OSA and hypertension have marked impairment of FMD, independent of hypoxia exposure, which is associated with increased sEng.Copyright Ó 2013, SciBioIMed.Org, Published by Reed Elsevier India Pvt. Ltd. All rights reserved. Key MessagesObstructive sleep apnea is a highly prevalent disorder with associated high morbidity and mortality. Obstructive sleep apnea is now considered as one of the causes of systemic hypertension. No all patients with obstructive sleep apnea develop hypertension. There appears to be divergent responses to apnea-associated hypoxia. In this article a group of patients with severe obstructive sleep apnea and hypoxia exposure during sleep had normal blood pressure and relatively preserved endothelial-dependent vasodilatory capacity. A comparable group of patients with similar apnea severity and hypoxia exposure had marked impairment in endothelial-dependent vasodilatory capacity and hypertension. This group had significantly elevated circulating levels of soluble endoglin, an angiogenesis inhibitor, with known effect on endothelial function and development of hypertension. It is conceivable that inflammatory state of obstructive sleep apnea provokes release of angiogenesis inhibitors causing downstream perturbation of endothelial...

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“…Through positive effects on vascular tone and glomerular capillary health, vascular endothelial growth factor (VEGF) and placental growth factor (PGF) are necessary for normal pregnancy (2)(3)(4). In PE, these proteins are antagonized by excessive placental production of soluble fms-like tyrosine kinase-1 (sFLT1), a splice variant of the VEGF receptor (2,3), and in later pregnancy, by soluble endoglin (sENG), a soluble form of a transforming growth factor beta (TGFB1) receptor that prevents binding of TGFB1 to membrane-bound endoglin (5). The report by Kumasawa et al (6) in PNAS describes the use of a mouse model in which placenta-specific expression of human sFLT1 is present from the time of implantation.…”

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confidence: 99%

Preeclampsia: Animal models for a human cure

Aubuchon

Schulz

Schust

2011

Proc. Natl. Acad. Sci. U.S.A.

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The effect of over-expression of sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice

Cited by 195 publications

References 44 publications

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

A Maternally Sequestered, Biopolymer‐Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia

Endothelial dysfunction and hypertension in obstructive sleep apnea – Is it due to intermittent hypoxia?

Preeclampsia: Animal models for a human cure

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