Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia

Burke, Suzanne D.; Zsengellér, Zsuzsanna K.; Khankin, Eliyahu V.; Lo, Agnes S.; Rajakumar, Augustine; DuPont, Jennifer J.; McCurley, Amy; Moss, M. Elizabeth; Zhang, Dongsheng; Clark, Christopher D.; Wang, Alice; Seely, Ellen W.; Kang, Peter M.; Stillman, Isaac E.; Jaffe, Iris Z.; Karumanchi, S. Ananth

doi:10.1172/jci83918

Cited by 123 publications

(120 citation statements)

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“…Furthermore, it has recently been shown that sFlt-1 may be directly inducing hypertension in preeclampsia by impairing eNOS phosphorylation. 7 We examined whether PPIs may be inducing vasorelaxation via the eNOS pathway. When we treated HUVECs with esomeprazole ( Figure 4A), there was a significant increase in phosphorylated eNOS (p-eNOS, the active form).…”

Section: Proton Pump Inhibitors May Be Promoting Vasodilation By Modumentioning

confidence: 99%

“…5 Furthermore, recent evidence suggests that sFlt-1 may induce hypertension by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and increasing angiotensin II sensitivity. 7 sENG shares sequence homology with the extracellular domain of full-length membrane-bound endoglin, a coreceptor that facilitates transforming growth factor receptor-β1 and transforming growth factor receptor-β3 signaling in endothelial cells. Like sFlt-1, sENG also antagonizes endothelial receptor signaling by competing with full-length endoglin, decreasing its ability to bind with its coreceptors to maintain vessel homeostasis.…”

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confidence: 99%

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Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

et al. 2017

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Preeclampsia is a severe complication of pregnancy. Antiangiogenic factors soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin are secreted in excess from the placenta, causing hypertension, endothelial dysfunction, and multiorgan injury. Oxidative stress and vascular inflammation exacerbate the endothelial injury. A drug that can block these pathophysiological steps would be an attractive treatment option. Proton pump inhibitors (PPIs) are safe in pregnancy where they are prescribed for gastric reflux. We performed functional studies on primary human tissues and animal models to examine the effects of PPIs on sFlt-1 and soluble endoglin secretion, vessel dilatation, blood pressure, and endothelial dysfunction. PPIs decreased sFlt-1 and soluble endoglin secretion from trophoblast, placental explants from preeclamptic pregnancies, and endothelial cells. They also mitigated tumor necrosis factor-α–induced endothelial dysfunction: PPIs blocked endothelial vascular cell adhesion molecule-1 expression, leukocyte adhesion to endothelium, and disruption of endothelial tube formation. PPIs decreased endothelin-1 secretion and enhanced endothelial cell migration. Interestingly, the PPI esomeprazole vasodilated maternal blood vessels from normal pregnancies and cases of preterm preeclampsia, but its vasodilatory effects were lost when the vessels were denuded of their endothelium. Esomeprazole decreased blood pressure in a transgenic mouse model where human sFlt-1 was overexpressed in placenta. PPIs upregulated endogenous antioxidant defenses and decreased cytokine secretion from placental tissue and endothelial cells. We have found that PPIs decrease sFlt-1 and soluble endoglin secretion and endothelial dysfunction, dilate blood vessels, decrease blood pressure, and have antioxidant and anti-inflammatory properties. They have therapeutic potential for preeclampsia and other diseases where endothelial dysfunction is involved.

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Section: Proton Pump Inhibitors May Be Promoting Vasodilation By Modumentioning

confidence: 99%

mentioning

confidence: 99%

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

et al. 2017

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“…Overexpression studies of sFlt1 in pregnant mice induced angiotensin II sensitivity by impairing endothelial nitric oxide synthase (eNOS) phosphorylation and increasing oxidative stress. 34 These alterations in NO production and bioavailability are observed in women with preeclampsia. Another component that may play a role in increased ANG II sensitivity during preeclampsia is a decrease in the G- protein regulating protein RGS5 35 .…”

Section: Discussionmentioning

confidence: 99%

Agonistic Autoantibodies to the Angiotensin II Type 1 Receptor Enhance Angiotensin II–Induced Renal Vascular Sensitivity and Reduce Renal Function During Pregnancy

et al. 2016

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Preeclampsia is a multisystemic disorder that is characterized by new-onset hypertension that usually occurs in the third trimester of pregnancy. 1,2 It is estimated that between 3% and 5% of pregnant women in the United States each year have preeclampsia. Preeclampsia is the leading cause of preterm birth, morbidity, and mortality for the mother and the fetus. 1,2Women with preeclampsia have elevated levels of the angiotensin II type 1 receptor autoantibodies (AT1-AA), oxidative stress, reduced renal function, and increased angiotensin II (ANG II) sensitivity.3-8 AT1-AAs in preeclampsia bind with a high affinity to the 7 amino acid sequence on the second extracellular loop of the AT1 receptor, in which it activates the AT1 receptor, increases intracellular calcium levels, and stimulates activation of intracellular mean arterial pressure/ERK kinase and tumor necrosis factor-α pathways similar to ANG II. [9][10][11][12][13] Several studies from our laboratory and others have demonstrated the important role of AT1-AAs in the pathophysiology of preeclampsia. In vitro studies with vascular smooth muscle and trophoblast cells demonstrate increased tissue factor VII and tissue factor activity, reactive oxygen species (ROS), NADPH oxidase components, and activation of NFκβ when incubated with AT1-AAs.13-15 Furthermore, human umbilical vein endothelial cells incubated for 6 hours with the AT1-AAs drastically increased endothelin-1 protein expression. 16 In vivo studies, in which isolated human and rodent AT1-AAs administered to rats during pregnancy, increased blood pressure, oxidative stress, renal artery resistant index, and several circulating factors associated with preeclampsia, such as soluble fms-like tyrosine kinase 1, sEng, endothelin-1, and endothelial microparticles. 7,[16][17][18][19][20][21][22] Thus, all these studies taken together confirm the critical role of AT1-AAs in causing many of the common characteristics of preeclampsia observed in women. 7,[16][17][18][19][20][21][22] Another characteristic shared by women with preeclampsia is increased sensitivity to ANG II, demonstrated years ago by Gant et al. 8 In Gant et al's 8 studies, young women between ages 13 and 17 years, with majority being black American women, were infused with various doses of ANG II until their diastolic blood pressure increased by 20 mm Hg. 11 In this study, they found that women destined to become preeclamptic displayed an increase in blood pressure at lower concentrations of ANG II versus those who had a normal pregnancy. From this early study, it was established that women with preeclampsia have increased sensitivity to ANG II from as early as 22 weeks of gestation until term. 11Abstract-Preeclamptic women produce agonistic autoantibodies to the angiotensin II type 1 receptor (AT1-AA) and exhibit increased blood pressure (mean arterial pressure), vascular sensitivity to angiotensin II (ANG II), and display a decrease in renal function. The objective of this study was to examine the renal hemodynamic changes during pregnancy i...

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“…More specific, a strong correlation between plasma levels of soluble form of Flt-1 and preeclampsia has been reported in several studies in both pregnant animals and women [20, 21]. More recently, Burke et al have demonstrated that soluble Flt-1 promotes vasoconstriction which is characteristic of preeclampsia by increasing angiotensin II sensitivity [22]. The current experiments explore a novel mechanism which may explain the anti angiogenic properties of sFlt-1, namely, a failure to stimulate arginine transport and hence NO generation.…”

Section: Discussionmentioning

confidence: 98%

Vascular Endothelial Growth Factor Augments Arginine Transport and Nitric Oxide Generation via a KDR Receptor Signaling Pathway

Shashar¹,

Chernichovski²,

Pasvolsky³

et al. 2017

Kidney Blood Press Res

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Background/Aims: Vascular endothelial growth factor (VEGF) is an endothelium-specific peptide that stimulates angiogenesis via two receptor tyrosine kinases, Flt-1 and KDR. Endothelial nitric oxide synthase (eNOS) plays a major role in VEGF signaling. Delivery of arginine to membrane bound eNOS by the cationic amino acid transporter-1 (CAT-1) has been shown to modulate eNOS activity. The current studies were designed to test the hypothesis that VEGF enhances eNOS activity via modulation of arginine transport by CAT-1. Methods: Using radio-labeled arginine, {[³H] L-arginine} uptake was determined in human umbilical vein endothelial cells (HUVEC) following incubation with VEGF with and without silencing the VEGF receptors Flt-1 or KDR. Subsequently, western blotting for CAT-1, PKCα, ERK 1/2, JNK, and their phosphorylated forms were performed. NO generation was measured by the Griess reaction. Results: VEGF (50 and 100 ng/ml) significantly augmented endothelial arginine transport in a time dependent manner, an effect which was prevented by Sunitinib (2 µM), a multi targeted receptor tyrosine kinase inhibitor. The increase in arginine transport velocities by VEGF was not affected by silencing Flt-1 while silencing KDR abrogated VEGF effect. Furthermore, incubating cells with 50 and 100 ng of VEGF for 30 minutes significantly augmented CAT-1 abundance. The expression of PKC-α, JNK, and ERK1/2 and their phosphorylated forms were unchanged following incubation of HUVEC with VEGF. The concentration of NO2/NO3 following incubation with VEGF was significantly higher than from untreated cells. This increase was significantly attenuated by silencing KDR. Conclusions: VEGF increases arginine transport via modulation of CAT-1 in endothelial cells. This effect is exclusively dependent on KDR rather than Flt-1.

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Soluble fms-like tyrosine kinase 1 promotes angiotensin II sensitivity in preeclampsia

Cited by 123 publications

References 77 publications

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

Proton Pump Inhibitors Decrease Soluble fms-Like Tyrosine Kinase-1 and Soluble Endoglin Secretion, Decrease Hypertension, and Rescue Endothelial Dysfunction

Agonistic Autoantibodies to the Angiotensin II Type 1 Receptor Enhance Angiotensin II–Induced Renal Vascular Sensitivity and Reduce Renal Function During Pregnancy

Vascular Endothelial Growth Factor Augments Arginine Transport and Nitric Oxide Generation via a KDR Receptor Signaling Pathway

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