Enhancement of trophoblast differentiation and survival by low molecular weight heparin requires heparin-binding EGF-like growth factor

Bolnick, Alan; Bolnick, Jay M.; Kohan-Ghadr, Hamid Reza; Kilburn, Brian A.; Pasalodos, Omar J.; Singhal, Pankaj; Dai, Jing; Diamond, Michael P.; Armant, D. Randall; Drewlo, Sascha

doi:10.1093/humrep/dex069

Cited by 28 publications

(25 citation statements)

References 63 publications

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“…This was accompanied by an increase in PlGF levels in the conditioned media; while the mechanism has not been well-explored, heparin could potentially elevate PlGF release by promoting de novo synthesis, stimulating release of intracellular stores, or displacing cell-surface heparin-binding PlGF isoforms, such as PlGF-2 or PlGF-4. Previous investigators have also shown that LMWH enhances trophoblast differentiation and survival [28, 29] and promotes extravillous trophoblast invasion [30]. Collectively, these data support the hypothesis that LMWH favorably influences placental development and normalizes angiogenic protein release, which may subsequently alleviate the systemic endothelial dysfunction evident in women with preeclampsia.…”

Section: Discussionsupporting

confidence: 80%

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia†

Wat

Hawrylyshyn

Baczyk

et al. 2018

Biology of Reproduction

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Low molecular weight heparin (LMWH) is being investigated as a potential preventative therapy against preeclampsia. There is evidence suggesting that LMWH may prevent preeclampsia through anticoagulation-independent mechanisms. In this study, we compared the in vitro placental, endothelial, and anti-inflammatory effects of a LMWH (dalteparin) with a non-anticoagulant, glycol-split heparin derivative (gsHep). In contrast with dalteparin, gsHep did not interact with antithrombin III, possess significant anti-Factor Xa activity, or significantly prolong in vitro plasma clotting time. However, dalteparin and gsHep were otherwise mechanistically similar, both interacting with soluble fms-like tyrosine kinase-1 (sFlt1) and promoting secretion of the pro-angiogenic protein placental growth factor, but not the anti-angiogenic sFlt1, from healthy placental villous explants. Placental explant media pre-treated with dalteparin or gsHep significantly stimulated endothelial cell tube formation compared to untreated explants. Lastly, dalteparin and gsHep both significantly suppressed inflammation by inhibiting complement activation and leukocyte adhesion to endothelial cells that were activated using serum from preeclamptic women. Our data suggest that non-anticoagulant heparin derivatives may be utilized as a tool to distinguish the anticoagulationindependent mechanisms of LMWH, and provide insight into the role of anticoagulation in the prevention of preeclampsia.

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Section: Discussionsupporting

confidence: 80%

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia†

Wat

Hawrylyshyn

Baczyk

et al. 2018

Biology of Reproduction

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“…Similarly, Sildenafil citrate (Viagra) applied to H/R HTR-8/SVneo cells can promote cell survival, if in the presence of NO and cGMP [ 33 ]. Oxidative stress-induced apoptosis can also be attenuated by HBEGF treatment in first trimester placental explants, as well as on the HTR-8/SVneo cells [ 34 ]. In these cells, exposure to oxygen peroxide induced down-regulation of HLA-G expression, a trophoblast immunomodulatory molecule that facilitates implantation and placental development [ 21 ].…”

Section: Cellular Sources Of Oxidative Stress In the Human Placentmentioning

confidence: 99%

Oxidative Stress in Preeclampsia and Placental Diseases

Aouache

Biquard

Vaiman

et al. 2018

IJMS

410

259

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Preeclampsia is a persistent hypertensive gestational disease characterized by high blood pressure and proteinuria, which presents from the second trimester of pregnancy. At the cellular level, preeclampsia has largely been associated with the release of free radicals by the placenta. Placenta-borne oxidative and nitrosative stresses are even sometimes considered as the major molecular determinants of the maternal disease. In this review, we present the recent literature evaluating free radical production in both normal and pathological placentas (including preeclampsia and other major pregnancy diseases), in humans and animal models. We then assess the putative effects of these free radicals on the placenta and maternal endothelium. This analysis was conducted with regard to recent papers and possible therapeutic avenues.

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“…Enoxaparin‐treated EVT‐like cells also underwent integrin switching from α 6 β 4 to α 1 β 1 , which is associated with increased invasiveness. This heparin effect was dependent on heparin‐binding epidermal growth factor signaling . In healthy pregnant rats, LMWH reduced decidual expression of E‐cadherin, a cell adhesion molecule (CAM) whose level is elevated in pre‐eclamptic placentas and that is associated with reduced invasive phenotypes .…”

Section: Potential Non‐anticoagulant Mechanisms Of Heparin In Pre‐eclmentioning

confidence: 99%

“…In addition to stimulating proliferation, heparin also protects against apoptosis of trophoblasts by increasing expression of the antiapoptotic factor Bcl‐2 . Heparin‐binding epidermal growth factor is also important for this cell survival mechanism , the production of which is stimulated by LMWH treatment . These positive effects on placental development impact on overall function, as demonstrated by elevated secretion of human chorionic gonadotropin and PlGF from LMWH‐treated placental villous explants .…”

Section: Potential Non‐anticoagulant Mechanisms Of Heparin In Pre‐eclmentioning

confidence: 99%

Molecular actions of heparin and their implications in preventing pre‐eclampsia

Wat

Audette

Kingdom

2018

Journal of Thrombosis and Haemostasis

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Pre-eclampsia, a hypertensive disorder of pregnancy, continues to be a significant cause of global maternal morbidity. Low-dose aspirin remains the only standard-of-care prophylactic therapy for preventing pre-eclampsia, but is limited in efficacy. Heparin and its derivatives may further enhance the efficacy of aspirin therapy to prevent pre-eclampsia, but the mechanisms mediating this augmentative effect are not known. Although heparin is an anticoagulant agent, it also possesses many anticoagulant-independent properties that may be relevant in the prevention of pre-eclampsia, including effects on placental, vascular and inflammatory function. This review summarizes the non-anticoagulant properties of heparin, and extrapolates how these actions may influence the trajectory of pre-eclampsia pathogenesis as a means of pathway-specific therapy.

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Enhancement of trophoblast differentiation and survival by low molecular weight heparin requires heparin-binding EGF-like growth factor

Abstract: This research was supported by grants from the National Institutes of Health (HD071408 and HL128628), the March of Dimes, and the W. K. Kellogg Foundation. There were no conflicts or competing interests.

Cited by 28 publications

References 63 publications

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia†

Effects of glycol-split low molecular weight heparin on placental, endothelial, and anti-inflammatory pathways relevant to preeclampsia†

Oxidative Stress in Preeclampsia and Placental Diseases

Molecular actions of heparin and their implications in preventing pre‐eclampsia

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