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      Angiogenic Effect of Pravastatin Alone and with Sera from Healthy and Complicated Pregnancies Studied by in vitro Vasculogenesis/Angiogenesis Assay

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          Abstract

          Objective: To determine the direct effect of pravastatin on angiogenesis and to study the interaction between pravastatin and maternal sera from women with early- or late-onset pre-eclampsia (PE), intrauterine growth restriction, or healthy pregnancy. Methods: We collected 5 maternal serum samples from each group. The effect of pravastatin on angiogenesis was assessed with and without maternal sera by quantifying tubule formation in a human-based in vitro assay. Pravastatin was added at 20, 1,000, and 8,000 ng/mL concentrations. Concentrations of angiogenic and inflammatory biomarkers in serum and in test medium after supplementation of serum alone and with pravastatin (1,000 ng/mL) were measured. Results: Therapeutic concentration of pravastatin (20 ng/mL) did not have significant direct effect on angiogenesis, but the highest concentrations inhibited angiogenesis. Pravastatin did not change the levels of biomarkers in the test media. There were no changes in angiogenesis when therapeutic dose of pravastatin was added with maternal sera, but there was a trend to wide individual variation towards enhanced angiogenesis, particularly in the early-onset PE group. Conclusions: At therapeutic concentration, pravastatin alone or with maternal sera has no significant effect on angiogenesis, but at high concentrations the effect seems to be anti-angiogenic estimated by in vitro assay.

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          Most cited references30

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          Effectiveness-based guidelines for the prevention of cardiovascular disease in women--2011 update: a guideline from the american heart association.

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            Hypertensive pregnancy disorders and subsequent cardiovascular morbidity and type 2 diabetes mellitus in the mother.

            Minimal data exist concerning the relationship between hypertensive pregnancy disorders and various subsequent cardiovascular events and the effect of type 2 diabetes mellitus on these. In a registry-based cohort study, we identified women delivering in Denmark from 1978 to 2007 with a first singleton (n=782 287) and 2 first consecutive singleton deliveries (n=536 419). The exposures were gestational hypertension and mild and severe preeclampsia. We adjusted for preterm delivery, small for gestational age, placental abruption, and stillbirth and, in a second model, we also adjusted for the development of type 2 diabetes mellitus. The end points were subsequent hypertension, ischemic heart disease, congestive heart failure, thromboembolic event, stroke, and type 2 diabetes mellitus. The risk of subsequent hypertension was increased 5.31-fold (range: 4.90 to 5.75) after gestational hypertension, 3.61-fold (range: 3.43 to 3.80) after mild preeclampsia, and 6.07-fold (range: 5.45 to 6.77) after severe preeclampsia. The risk of subsequent type 2 diabetes mellitus was increased 3.12-fold (range: 2.63 to 3.70) after gestational hypertension and 3.68-fold (range: 3.04 to 4.46) after severe preeclampsia. Women having 2 pregnancies both complicated by preeclampsia had a 6.00-fold (range: 5.40 to 6.67) increased risk of subsequent hypertension compared with 2.70-fold (range: 2.51 to 2.90) for women having preeclampsia in their first pregnancy only and 4.34-fold (range: 3.98 to 4.74) for women having preeclampsia in their second pregnancy only. The risk of subsequent thromboembolism was 1.03-fold (range: 0.73 to 1.45), 1.53-fold (range: 1.32 to 1.77), and 1.91-fold (range: 1.35 to 2.70) increased after gestational hypertension and mild and severe preeclampsia, respectively. Thus, hypertensive pregnancy disorders are strongly associated with subsequent type 2 diabetes mellitus and hypertension, the latter independent of subsequent type 2 diabetes mellitus. The severity, parity, and recurrence of these hypertensive pregnancy disorders increase the risk of subsequent cardiovascular events.
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              Statins have biphasic effects on angiogenesis.

              Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo. Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 micromol/L) but significantly inhibited at high statin concentrations (0.05 to 1 micromol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg x kg(-1) x d(-1)) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg x kg(-1) x d(-1)). Despite the fact that high-dose statin treatment was effective at reducing lipid levels in hyperlipidemic apolipoprotein E-deficient mice, it impaired rather than enhanced angiogenesis. Finally, high-dose cerivastatin decreased tumor growth and tumor vascularization in a murine Lewis lung cancer model. HMG-CoA reductase inhibition has a biphasic dose-dependent effect on angiogenesis that is lipid independent and associated with alterations in endothelial apoptosis and vascular endothelial growth factor signaling. Statins have proangiogenic effects at low therapeutic concentrations but angiostatic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate. At clinically relevant doses, statins may modulate angiogenesis in humans via effects on geranylated proteins.
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                Author and article information

                Journal
                JVR
                J Vasc Res
                10.1159/issn.1018-1172
                Journal of Vascular Research
                S. Karger AG
                1018-1172
                1423-0135
                2021
                May 2021
                11 February 2021
                : 58
                : 3
                : 139-147
                Affiliations
                [_a] aDepartment of Obstetrics and Gynaecology, Tampere University Hospital, Tampere, Finland
                [_b] bFICAM, Finnish Centre for Alternative Methods, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
                [_c] cFaculty of Medicine and Health Technology, Tampere University, Tampere, Finland
                Author notes
                *Anita Virtanen, Department of Obstetrics and Gynaecology, Tampere University Hospital, PL 2000, FI –33520 Tampere (Finland), anita.virtanen@fimnet.fi
                Article
                512831 J Vasc Res 2021;58:139–147
                10.1159/000512831
                33571991
                177efd53-8644-4750-b23a-c94b101bb239
                © 2021 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                History
                : 20 April 2020
                : 02 November 2020
                Page count
                Figures: 3, Tables: 4, Pages: 9
                Categories
                Research Article

                General medicine,Neurology,Cardiovascular Medicine,Internal medicine,Nephrology
                In vitro angiogenesis,Angiogenic biomarkers,Intrauterine growth restriction,Pravastatin,Pre-eclampsia

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