One Step Closer to a Cure for Preeclampsia?

Abstract

HomeHypertensionVol. 76, No. 4One Step Closer to a Cure for Preeclampsia? Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessEditorialPDF/EPUBOne Step Closer to a Cure for Preeclampsia?Boosting the Natural Affinity of VEGF (Vascular Endothelial Growth Factor) to sFlt (Soluble fms-Like Tyrosine Kinase)-1 Ana Sofia Cerdeira, Manu Vatish, Edouard Lecarpentier Ana Sofia CerdeiraAna Sofia Cerdeira Correspondence to Ana Sofia Cerdeira, Nuffield Department of Women’s & Reproductive Health University of Oxford, Level 3, Women’s Center, John Radcliffe Oxford University Hospital, Oxford, OX3 9DU, United Kingdom. Email E-mail Address: [email protected] From the Nuffield Department of Women’s & Reproductive Health University of Oxford, United Kingdom (A.S.C., M.V.) Search for more papers by this author , Manu VatishManu Vatish https://orcid.org/0000-0002-6012-2574 From the Nuffield Department of Women’s & Reproductive Health University of Oxford, United Kingdom (A.S.C., M.V.) Search for more papers by this author , Edouard LecarpentierEdouard Lecarpentier https://orcid.org/0000-0002-1290-2939 Department of Obstetrics and Gynecology, Centre Hospitalier Intercommunal de Creteil, University Paris Est Créteil, France (E.L.). Search for more papers by this author Originally published9 Sep 2020https://doi.org/10.1161/HYPERTENSIONAHA.120.15112Hypertension. 2020;76:1081–1083This article is a commentary on the followingAffinity-Enhanced Multimeric VEGF (Vascular Endothelial Growth Factor) and PlGF (Placental Growth Factor) Variants for Specific Adsorption of sFlt-1 to Restore Angiogenic Balance in PreeclampsiaSee related article, pp 1176–1184Preeclampsia is a multisystem hypertensive disorder of pregnancy that affects 4% to 8% of pregnancies worldwide. It originates from a dysfunctional placenta, and once the disease is recognized, the only effective treatment is to remove the placenta by expediting delivery irrespective of gestational age, resulting in substantial neonatal morbidity and mortality. If delivery is significantly delayed, maternal complications including death can occur.1 Abnormal endothelial function is the hallmark of preeclampsia leading to the maternal syndrome (hypertension and multiorgan disease). In this issue of Hypertension Matin et al2 propose a promising therapeutic intervention for preeclampsia.Recently, sFlt-1 (soluble fms-like tyrosine kinase 1) has been identified as a key molecule released from the placenta driving this endothelial dysfunction.3 sFlt-1 (a soluble form of the Flt-1 receptor, also known as VEGFR [vascular endothelial growth factor receptor]-1) is an antiangiogenic factor, which binds to PlGF (placental growth factor) and VEGF (vascular endothelial growth factor)—important trophic signals for the endothelium.3 Thus, excessive circulating sFlt-1 creates an angiogenic imbalance by reducing free PlGF and VEGF which adversely affects endothelial homeostasis. Studies in animal models show that when sFlt-1 is administered to rodents it induces clinical features consistent with preeclampsia.3 In patients with preeclampsia, sFlt-1 is significantly increased and free PlGF is correspondingly decreased often several weeks in advance of disease manifestation. Measurement of sFlt-1/PlGF ratio in the maternal circulation is used clinically in several countries to predict or rule out the development of disease.4Given this angiogenic imbalance, strategies to correct it are attractive as they offer the potential to attenuate disease severity and safely prolong gestation. Some authors have removed sFlt-1 from the circulation using plasma apheresis, whereas others have proposed a reduction of placental expression of sFlt-1 or delivery of PlGF.5Matin et al,2 adapted the natural high-affinity binding of VEGF to sFlt-1 and developed a novel mechanism for sFlt-1 depletion in the blood of patients with preeclampsia. They generated VEGF multimers with higher affinity to sFlt-1 than wild-type VEGF and linked these multimers to an agarose matrix for sFlt-1 apheresis. This strategy allowed for a significant depletion of sFlt-1 associated with a concomitant release of endogenous VEGF and PlGF.2 In addition to reducing sFlt-1, the release of VEGF and PlGF could also redress the angiogenic imbalance because VEGF activates VEGFR-2 (important for endothelial health) and PlGF does not (by binding VEGFR-1, PlGF increases VEGF availability to bind VEGFR-2).Extracorporeal removal of sFlt-1 has been safely performed previously (by this group and others) with promising results.6,7 Studies using an apheresis system (with a noncompetitive negatively charged dextran sulfate column which captured positively charged sFlt-1) were able to deplete sFlt-1 in the maternal circulation and safely prolong the gestation by ≈15 days in treated women compared with 3 to 5 days in untreated preeclampsia controls.6 The goal of this pilot study was to assess safety and potential efficacy of therapeutic apheresis. A modest reduction of sFlt-1 levels 18% (maximum 31%) was sought; the consequences of larger depletions are unknown.6 VEGF and PlGF levels were not reported. This apheresis approach was based on charge and not on epitope-specific binding and targeting of sFlt-1.The first proof of concept of a selective and competitive apheresis approach to reduce circulating sFlt-1, whereas increasing free PlGF was reported by Trapiella-Alfonso et al.8 To alter the equilibrium of sFlt-1/PlGF binding, they grafted magnetic beads with biotinylated truncated form of VEGF, which has a >10 fold greater affinity for sFlt-1 than does PlGF. This truncated VEGF (VEGF-95) was able to effectively capture sFlt-1 and liberate PlGF, leading to a 68% reduction of the sFlt-1/PlGF ratio in plasma from women with preeclampsia.8 The liberation of PlGF was believed capable of potentiating its proangiogenic effects on maternal endothelium. Matin et al2 have elegantly extended this concept by developing novel high-affinity full-length VEGF multimers and binding these multimers to columns with a less immunogenic profile leading to a significant depletion of sFlt-1 with concomitant release of PlGF and VEGF (Figure)Download figureDownload PowerPointFigure. Competitive biomimetic approach using VEGF (vascular endothelial growth factor) multimers to capture circulating sFlt (soluble fms-like tyrosine kinase)-1 while releasing free PlGF (placental growth factor) and VEGF.With the aid of computer modeling, Matin et al2 generated single-chain VEGF165 dimers that complexed into multimeric tetramers. These VEGF165 multimers displayed a 1.4 fold higher affinity for sFlt-1 compared with monomeric VEGF165 or antibodies to sFlt-1 and could competitively release sFlt-1 bound to PlGF and VEGF.Next, the VEGF multimers were immobilized on aldehyde-activated agarose apheresis columns and examined for their efficacy in removing sFlt-1 from serum of patients with suspected preeclampsia and high sFlt-1/PlGF ratios. This revealed a mean sFlt-1 reduction of 88%, with concomitant release of PlGF (20-fold) and VEGF (9-fold) compared to initial levels. The possibility that this excess PlGF and VEGF might be leakage from the column was excluded. This compares to a 77.2% reduction with monomeric VEGF and sFlt-1 antibody which, in the latter case, did not result in release of either PlGF or VEGF.2These large amounts of PlGF at the column outlet obtained with samples from preeclamptic women support the hypothesis that sFlt-1, released in excess by the syncytiotrophoblast during preeclampsia, is the main cause of the decrease in circulating levels of free PlGF. The significant release of VEGF could also be due to release of VEGF bound to soluble receptors other than sFlt-1 (eg, soluble VEGF receptor 2; soluble neuropilin).8 These may also bind VEGF multimers on the column and contribute to VEGF release, although this was not specifically assessed in this study. Understanding the contribution of the different VEGF receptors might lead to a more specific sFlt-1 depletion. Moreover, VEGF165 is one of the several VEGF-A isoforms (the most abundant and considered the prototypical VEGF-A molecule). These are generated by alternative splicing and differ on their neuropilin and extracellular matrix binding. As opposed to other isoforms, VEGF165 has both neuropilin and extracellular matrix binding and could, therefore, also release VEGF bound to soluble neuropilin. It is also possible that different VEGF-A isoforms could present different macromolecular complex assemblies and lead to a different proportion of sFlt-1 and VEGF release.The authors have applied an understanding of the affinity of sFlt-1 to VEGF and adapted this in an elegant and thoroughly conducted study.2 These data hold the promise of development of treatments other than delivery. The concomitant release of both VEGF and PlGF is a particularly interesting corollary of their approach since it might improve angiogenic imbalance; however, some caution should be applied.A substantial in vivo release of PlGF and VEGF, in particular, may be problematic. In normal pregnancies, the amount of free VEGF is significantly less than free PlGF.3 First described as vascular permeability factor, VEGF is a pleiotropic molecule that affects many cell systems, in particular, the vasculature. VEGF has a direct vasodilatory effect by a nitric oxide–dependent mechanism and can, therefore, modulate systemic blood pressure. As Matin et al2 state, the levels of VEGF and PlGF released have not been reported to cause hemodynamic instability in animal models; however, this needs to be explored before moving into human studies. Furthermore, excess release of VEGF might have other detrimental effects systemically (eg, increased vascular permeability, immune cell modulation, and possibly placental function).9,10 As the authors show, VEGF release correlates with the amount of sFlt-1 removal. This system can be fine-tuned to mitigate some of these facets and will need optimizing before moving into human trials.In contrast to current clinical practice (close observation and delivery when either the fetus or the mother deteriorate), strategies to prolong pregnancy have the potential to significantly improve fetal outcomes, in particular at early gestations where every additional day in utero counts. Specific removal of the pathogenic molecule sFlt-1 could allow this without compromising maternal condition. Further studies are needed but this work from Matin et al2 holds significant promise for the future.Sources of FundingA.S. Cerdeira is supported by a National Institute for Health Research Clinical LectureshipFootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Ana Sofia Cerdeira, Nuffield Department of Women’s & Reproductive Health University of Oxford, Level 3, Women’s Center, John Radcliffe Oxford University Hospital, Oxford, OX3 9DU, United Kingdom. Email sofia.[email protected]ox.ac.uk