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      Angiogenesis, Lymphangiogenesis, and the Immune Response in South African Preeclamptic Women Receiving HAART

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          Abstract

          Purpose of the review: This review highlights the role of angiogenesis, lymphangiogenesis, and immune markers in human immunodeficiency virus (HIV)-associated preeclamptic (PE) pregnancies in an attempt to unravel the mysteries underlying the duality of both conditions in South Africa. Recent findings: Studies demonstrate that HIV-infected pregnant women develop PE at a lower frequency than uninfected women. In contrast, women receiving highly active anti-retroviral therapy (HAART) are more inclined to develop PE, stemming from an imbalance of angiogenesis, lymphangiogenesis, and immune response. Summary: In view of the paradoxical effect of HIV infection on PE development, this study examines angiogenesis, lymphangiogenesis, and immune markers in the highly HIV endemic area of KwaZulu-Natal. We believe that HAART re-constitutes the immune response in PE, thereby predisposing women to PE development. This susceptibility is due to an imbalance in the angiogenic/lymphangiogenic/immune response as compared to normotensive pregnant women. Further large-scale studies are urgently required to investigate the effect of the duration of HAART on PE development.

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          Most cited references125

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          Th1/Th2/Th17 and regulatory T-cell paradigm in pregnancy.

          T-helper (Th) cells play a central role in modulating immune responses. The Th1/Th2 paradigm has now developed into the new Th1/Th2/Th17 paradigm. In addition to effector cells, Th cells are regulated by regulatory T (Treg) cells. Their capacity to produce cytokines is suppressed by immunoregulatory cytokines such as transforming growth factor (TGF)-beta and interleukin (IL)-10 or by cell-to-cell interaction. Here, we will review the immunological environment in normal pregnancy and complicated pregnancy, such as implantation failure, abortion, preterm labor, and preeclampsia from the viewpoint of the new Th1/Th2/Th17 and Treg paradigms.
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            Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases.

            Vascular endothelial growth factors (VEGFs) belong to the platelet-derived growth factor supergene family, and they play central roles in the regulation of angiogenesis and lymphangiogenesis. VEGF-A, the major factor for angiogenesis, binds to two tyrosine kinase (TK) receptors, VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1), and regulates endothelial cell proliferation, migration, vascular permeability, secretion and other endothelial functions. VEGFR-2 exhibits a strong TK activity towards pro-angiogenic signals, whereas the soluble VEGFR-1 (sFlt-1) functions as an endogenous VEGF inhibitor. sFlt-1 is abnormally overexpressed in the placenta of preeclampsia patients, resulting in the major symptoms of the disease due to abnormal trapping of VEGFs. The VEGF-VEGFR system is crucial for tumour angiogenesis, and anti-VEGF-VEGFR molecules are now widely used in the clinical field to treat cancer patients. The efficacy of these molecules in prolonging the overall survival of patients has been established; however, some cancers do not respond well and reduced tumour sensitivity to anti-VEGF signals may occur after long-term treatment. The molecular basis of tumour refractoriness should be determined to improve anti-angiogenic therapy.
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              Angiopoietins in angiogenesis.

              Tie-1 and Tie-2 tyrosine kinase receptors are expressed specifically on vascular endothelial cells and on a certain subtype of macrophages implicated in angiogenesis, thus, they have been a major focus of angiogenesis research. Tie-1 and Tie-2 are essential for vascular maturation during developmental, physiological and pathological angiogenesis. Angiopoietin 1-4 (Ang-1-4) have been identified as bona fide ligands of the Tie-2 receptor, while Tie-1 remains an orphan receptor which is able to heterodimerize with Tie-2 and to modulate Tie-2 signal transduction. The most exhaustively studied angiopoietins are Ang-1 and Ang-2. Ang-1 is a critical player in vessel maturation and it mediates migration, adhesion and survival of endothelial cells. Ang-2 disrupts the connections between the endothelium and perivascular cells and promotes cell death and vascular regression. Yet, in conjunction with VEGF, Ang-2 promotes neo-vascularization. Hence, angiopoietins exert crucial roles in the angiogenic switch during tumor progression, and increased expression of Ang-2 relative to Ang-1 in tumors correlates with poor prognosis. Its central role in the regulation of physiological and pathological angiogenesis makes the angiopoietin/Tie signaling pathway a therapeutically attractive target for the treatment of vascular disease and cancer. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                30 July 2019
                August 2019
                : 20
                : 15
                : 3728
                Affiliations
                [1 ]Optics and Imaging Centre, Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa
                [2 ]Discipline of Obstetrics and Gynecology, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban 4013, South Africa
                [3 ]Women’s Health and HIV Research Group. Department of Obstetrics and Gynecology, School of Clinical Medicine, University of KwaZulu-Natal, Durban 4013, South Africa
                Author notes
                [* ]Correspondence: naickera@ 123456ukzn.ac.za (T.N.); phoswawendy@ 123456gmail.com (W.N.P.)
                [†]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0002-6648-8833
                Article
                ijms-20-03728
                10.3390/ijms20153728
                6696390
                31366152
                ee3dc97f-7290-450c-bea2-b7e5c0947f2b
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 17 April 2019
                : 22 May 2019
                Categories
                Review

                Molecular biology
                angiogenesis,highly active anti-retroviral therapy,human immunodeficiency virus,lymphangiogenesis,immune response,preeclampsia

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