Placental-Specific sFLT-1 e15a Protein Is Increased in Preeclampsia, Antagonizes Vascular Endothelial Growth Factor Signaling, and Has Antiangiogenic ActivityNovelty and Significance
In preeclampsia, the antiangiogenic factor soluble fms-like tyrosine kinase-1 (sFLT-1) is released from placenta into the maternal circulation, causing endothelial dysfunction and organ injury. A recently described splice variant, sFLT-1 e15a, is primate specific and the most abundant placentally derived sFLT-1. Therefore, it may be the major sFLT-1 isoform contributing to the pathophysiology of preeclampsia. sFLT-1 e15a protein remains poorly characterized: its bioactivity has not been comprehensively examined, and serum levels in normal and preeclamptic pregnancy have not been reported. We generated and validated an sFLT-1 e15a–specific ELISA to further characterize serum levels during pregnancy, and in the presence of preeclampsia. Furthermore, we performed assays to examine the bioactivity and antiangiogenic properties of sFLT-1 e15a protein. sFLT-1 e15a was expressed in the syncytiotrophoblast, and serum levels rose across pregnancy. Strikingly, serum levels were increased 10-fold in preterm preeclampsia compared with normotensive controls. We confirmed sFLT-1 e15a is bioactive and is able to inhibit vascular endothelial growth factor signaling of vascular endothelial growth factor receptor 2 and block downstream Akt phosphorylation. Furthermore, sFLT-1 e15a has antiangiogenic properties. sFLT-1 e15a decreased endothelial cell migration, invasion, and inhibited endothelial cell tube formation. Administering sFLT-1 e15a blocked vascular endothelial growth factor induced sprouts from mouse aortic rings ex vivo. We have demonstrated that sFLT-1 e15a is increased in preeclampsia, antagonizes vascular endothelial growth factor signaling, and has antiangiogenic activity. Future development of diagnostics and therapeutics for preeclampsia should consider targeting placentally derived sFLT-1 e15a.
Preeclampsia affects 5% to 8% of pregnancies. It is a significant contributor to global maternal and perinatal morbidity and mortality, responsible for an estimated 60 000 maternal deaths annually1 and far more neonatal losses. The only effective treatment is delivery of fetus and placenta.
In preeclampsia, the intermittently hypoxic placenta (caused by poor placental implantation) releases excessive antiangiogenic proteins into the maternal circulation.2 These cause widespread endothelial dysfunction that injures major maternal organs, including the kidneys, liver, and brain.2,3
An antiangiogenic factor central to the pathogenesis of preeclampsia is soluble fms-like tyrosine kinase-1 (sFLT-1), a splice variant of FLT-1 (vascular endothelial growth factor receptor 1 [VEGFR1]).4,5 Placentally derived sFLT-1 binds to VEGF and placental growth factor in the maternal circulation, preventing them from activating cognate receptors to promote vascular homeostasis.3
At least 4 splice variants of sFLT-1 have been described (Figure 1A).6–8 They share the extracellular domain of FLT-1 and differ at their C-terminal sequence. Two sFLT-1 variants are the most abundant and are the 2 main transcripts expressed in placenta.6 sFLT-1 i13 has a unique 28 amino acid C-terminal region and is generically expressed in many tissues, including placenta, endothelium, brain, heart, and kidneys. In contrast, sFLT-1 e15a (also known as sFLT-1 147 or sFLT-1 v26) is a recently described variant that has a unique 31 amino acid, serine-rich C-terminus. Interestingly, it is primate specific8 and principally produced in placenta,6 where ≤80% of all FLT-1 transcripts are spliced to become sFLT-1 e15a.6 Therefore, sFLT-1 e15a may be the major sFLT-1 isoform responsible for preeclampsia, a disease essentially unique to humans (with some case reports in primates9,10).
Despite the likely importance of sFLT-1 e15a in preeclampsia, it has not been well studied. Initial reports described increased sFLT-1 e15a mRNA with preeclampsia, not protein.6,7,11 To our knowledge, functional studies examining sFLT-1 e15a protein bioactivity have been limited to one experiment showing it competitively inhibits VEGF-induced activation (phosphorylation) of VEGFR2 in porcine endothelial cells.7 Furthermore, serum levels have not been reported. A possible explanation is the lack of commercially available reagents, notably an sFLT-1 e15a ELISA.
Here, we report the generation and validation of a specific sFLT-1 e15a ELISA. We show serum sFLT-1 e15a levels rise across pregnancy and are significantly elevated in severe preterm preeclampsia. Using purified sFLT-1 e15a protein, we also show sFLT-1 e15a is biologically active: it competes with VEGF to block VEGFR2 signaling, blocks VEGF-induced Akt phosphorylation, and inhibits endothelial cell migration, invasion, tube formation, and angiogenesis. Furthermore, it inhibits VEGF-induced endothelial sprouts from mouse aortic rings cultured ex vivo. Collectively, our work suggests that placentally derived sFLT-1 e15a may play a major role in the pathophysiology of preeclampsia.
Abbreviated Methods are presented here. Further details are available in the online-only Data Supplement.
Tissue and Serum Sample Collection
Placenta was collected from preterm (<34 weeks) pregnancies not complicated by preeclampsia (n=22) and those complicated by preterm preeclampsia (n=16). Ethics approval was obtained from The Human Research Ethics Committees at Mercy Health (Mercy Hospital for Women, Victoria, Australia). All participants provided written informed consent.
Serum samples were collected longitudinally from 22 women with normal pregnancies at 4 weekly intervals beginning from 16 weeks of gestation until 36 weeks of gestation. Serum samples were also collected from 30 cases of preterm preeclampsia at the same institution. Samples collected at 28 and 32 weeks from the longitudinal cohort (n=22 women) were used as controls to compare sFLT-1 levels with the preeclamptic cohort in this serum study.
Polyclonal Antibody Development
Unconjugated peptides for sFLT-1 e15a (KNNHKIQQEPELYTSTC) were produced (Auspep; Tullamarine, Australia) and conjugated to keyhole limpet hemocyanin and emulsed in incomplete Freund’s adjuvant and specific pathogen-free rabbits immunized (Invitrogen). Protein A purification was performed to isolate the IgG antibody component from the sera (Invitrogen).
sFLT-1 Variant Protein Production and Purification
For initial optimization of the sFLT-1 e15a ELISA (Figure 2A), sFLT-1 e15a protein was purified in house. FLAG-tagged sFLT-1 variant proteins were produced in a 293F mammalian cell system and FLAG-tagged proteins were purified using anti-FLAG M2 affinity resin (Sigma). For ELISA standards and functional studies, recombinant sFLT-1 e15a protein was obtained by custom order (Genscript, Piscataway, NJ).
A commercial sFLT-1 ELISA (R&D systems, NE, Minneapolis) was used to measure total sFLT-1. Commercially available primary antibodies used were sFLT-1 (AF321 and MAB321; R&D Systems), pAkt (ser-473; Sigma, Sydney, Australia), and Akt (Sigma). sFLT-1 i13 and VEGF protein were purchased (R&D Systems).
Western Analysis and Immunofluorescence for sFLT-1 e15a
To assess the specificity of the newly generated sFLT-1 e15a polyclonal, binding was assessed by Western blot following loading of either purified sFLT-1 i13 or sFLT-1 e15a. Immunofluorescence staining using the polyclonal antibody was performed on preterm control and preeclamptic placentas to assess sFLT-1 e15a localization.
Reverse Transcription–Polymerase Chain Reaction
RNA was extracted from tissue or cells using the RNeasy mini kit (Qiagen, Valencia, CA) and converted to cDNA using Applied Biosystems high capacity cDNA reverse transcriptase kit (Life technologies, Mulgrave, Australia) as per manufacturer guidelines.
sFLT-1splice variant mRNA expression was determined using variant primer sequences as previously published.11 All data were normalized to GAPDH (glyceraldehyde 3-phosphate dehydrogenase) as an internal control and calibrated against the average Ct (cycle threshold) of the control samples. The results were expressed as fold change relative to controls.
sFLT-1 e15a siRNA Treatment of Primary Trophoblast
Primary trophoblast was transfected with siRNAs targeting sFLT-1 e15a (custom order, Integrated DNA Technologies, San Diego, CA). Seventy-two hours post transfection, RNA was collected to analyze knockdown, and conditioned media were collected to measure sFLT-1 e15a and sFLT-1 by ELISA. Experiments were repeated 3× where each experiment was done in triplicate.
sFLT-1 and sFLT-1 e15a ELISA
Total sFLT-1 levels were determined using a commercially available ELISA (R&D Systems) in accordance with manufacturer’s instructions. We developed an sFLT-1 e15a–specific ELISA by coating the plate with a commercially available anti-FLT-1 antibody (MAB321; R&D Systems) at 4 μg/mL as the capture antibody, and our newly generated sFLT-1 e15a polyclonal antibody (G4635) at 10 μg/mL as the detection antibody. Purified sFLT-1 e15a protein was used to derive standard curves.
Functional Studies to Assess the Bioactivity of sFLT-1 e15a
Bioactivity was assessed using a Ba/F3 assay, where the cells have been engineered to require ongoing VEGFR1 signaling to survive.14 Ba/F3 cells were cultured in 12.5 ng/mL of human VEGF165 (R&D systems) plus serial dilutions of sFLT-1 e15a, heat inactivated sFLT-1 e15a, or recombinant sFLT-1 (R&D systems) ranging from 7.8–1000 ng/mL. Cell viability was assessed at 72 hours by MTS assay (Promega, Fitchburg).
To assess the effects of sFLT-1 on endothelial cell HUVEC migration and invasion, we used the xCELLigence system (Roche). This assay monitors experiments in real time. We examined the migration, and invasion through matrigel of HUVECs toward VEGF. We examined the effects of the following: (1) sFLT-1 e15a, (2) heat-inactivated sFLT-1 e15a, and (3) recombinant sFLT-1 (or i13, purchased from R&D systems). Doses ranged between 125 and 250 ng/mL.
We examined whether sFLT-1 e15a blocks VEGF-induced Akt phosphorylation by treating HUVECs with VEGF for 30 minutes±sFLT-1 e15a. The tissues were then collected, and both total and phosphorylated Akt were measured by Western blot followed by densitometric analysis.
We also examined whether sFLT-1 e15a blocked VEGF-induced aortic ring sprouting, as described by others.15 Aortic rings were collected from C57BL/6 mice and embedded in rat-tail collagen and treated with VEGF±sFLT-1 e15a or recombinant sFLT-1 (R&D systems). At 168 hours post plating, aortic rings were stained with calcein acetoxymethyl ester, and the number of microvessels (or sprouts) per aortic ring was counted.
sFLT-1 e15a Is Increased in Severe Preeclampsia and Is Expressed in Syncytiotrophoblast
We measured sFLT-1 e15a mRNA levels in placenta from 18 cases of preterm preeclampsia and 23 preterm normotensive controls (Table S1 in the online-only Data Supplement shows clinical details). There were no differences in gestational age between the 2 groups. Both sFLT-1 e15a (Figure 1B) and sFLT-1 i13 mRNA (Figure 1C) were increased in preeclampsia compared with controls. By expressing sFLT-1 variants as a ratio with mRNA coding full length FLT-1, we inferred that sFLT-1 e15a transcript abundance is approximately double sFLT-1 i13 mRNA (Figure 1D). Thus, our data confirm previous reports6 that sFLT-1 e15a mRNA is more abundant than sFLT-1 i13 in placenta.
To detect sFLT-1 e15a protein, we generated sFLT-1 e15a–specific polyclonal antibodies. We confirmed that the sFLT-1 e15a antibody specifically detects recombinant e15a, but not sFLT-1 i13, by immunoblotting (Figure 1E, G4635 is the polyclonal antibody we generated for sFLT-1 e15a). In contrast, we confirmed the commercially available sFLT-1 antibody (AF321) indiscriminately detected both sFLT-1 variants. This is expected because AF321 detects an epitope present on the extracellular portion of sFLT-1, which is present on all variants, as well as FLT-1.
Previously, it was shown by in situ hybridization that sFLT-1 e15a mRNA is expressed in the syncytiotrophoblast.7 Using the G4635 antibody, we performed immunofluorescence and verified that sFLT-1 e15a protein is indeed highly expressed in the syncytiotrophoblast layer of the placenta (Figure 1F–1H).
Development and Validation of an sFLT-1 e15a–Specific ELISA
We next generated an sFLT-1 e15a–specific sandwich ELISA. We used a commercial sFLT-1 antibody (MAB321) as the capture antibody and the sFLT-1 e15a–specific polyclonal (G4635) as the detection antibody. We spiked media with recombinant sFLT-1 e15a protein at serial dilutions and observed that our sFLT-1 e15a ELISA sensitively and linearly detects sFLT-1 e15a (Figure 2A). Furthermore, the ELISA did not detect sFLT-1 i13 spiked in at a higher concentration (1:50) than the top concentration of sFLT-1 e15a (1:100, Figure 2A).
Next, we confirmed that our newly generated ELISA detects endogenously produced sFLT-1 e15a protein secreted from placenta. We did this by silencing sFlt-1 e15a in primary trophoblast and measuring sFLT-1 e15a secreted into the conditioned media (Figure 2C and 2D). Our ELISA detected a 79% reduction in secreted sFLT-1 e15a levels, where sFlt-1 e15a was silenced. The commercially available sFLT-1 ELISA detected an 18% reduction in sFLT-1 (Figure 2E). We further validated the specificity of the capture (MAB321) and detection (pAb G4635) antibodies to detect sFLT-1 e15a, by performing an immunoprecipitation using MAB321, followed by Western blotting with G4635 on preeclamptic placental tissue. A specific band consistent with the expected size of sFLT-1 e15a was identified (Figure S1).
To further validate the robustness of our ELISA, we assessed the intraplate % coefficient of variance (% CV) by measuring sFLT-1 e15a levels in the same samples (3 different samples) and confirmed that it was <10%. We assessed the interplate % CV by measuring sFLT-1 in 3 different serum samples repeated on 3 separate ELISA plates. The interplate % CV was 5.6%, 7.5%, and 4.8%. These % CV suggests that our ELISA is robust and reliable in quantifying sFLT-1 e15a levels. Finally, we tested the accuracy of the ELISA at measuring known amounts of sFLT-1 e15a. Serial dilutions of sFLT-1 e15a were spiked into preeclamptic serum (ranging from 781–25 000 pg/mL) and assessed using the pAb ELISA. As shown in Figure S2, the expected versus actual reads were within 10% of one another, verifying the accuracy of the ELISA at measuring known amounts of sFLT-1 e15a within this range.
Hence, we have generated and validated an ELISA that specifically detects sFLT-1 e15a, but not sFLT-1 i13.
Serum sFLT-1 e15a Across Normal Pregnancy and in Preterm Preeclampsia
Using our newly generated sFLT-1 e15a ELISA, we measured sFLT-1 e15a in serum prospectively collected serially from a cohort of 22 women with healthy pregnancies who delivered at term (see Table S2 for clinical details). Similar to trends previously reported for total sFLT-1,5 serum sFLT-1 e15a levels also increased across gestation (Figure 3A).
We then measured sFLT-1 e15a levels in serum from 30 women diagnosed with preterm preeclampsia and 38 samples from healthy pregnancies (selected from 28- and 32-week samples obtained from the longitudinal cohort, ie, healthy women who delivered at term, see Table S2 for clinical details). Serum sFLT-1 e15a in the preeclamptic cohort was increased 10-fold compared with controls (Figure 3B). As expected, the commercial sFLT-1 ELISA (detects all variants) also identified a significant increase in sFLT-1 in the preeclamptic serum compared with controls (Figure 3C).
sFLT-1 e15a Inhibits VEGF Signaling and Decreases Phosphorylation of Akt
We next examined whether sFLT-1 e15a protein is bioactive. We coadministered VEGF and sFLT-1 e15a to Ba/F3 cells, which have been engineered to require ongoing VEGFR2 signaling to avoid cell death. Thus, if sFLT-1 e15a is bioactive and able to inhibit VEGF, it would lead to decreased VEGF signaling and consequently increased Ba/F3 cell death. Indeed, we found that sFLT-1 e15a decreased Ba/F3 cell viability in a dose-dependent manner (Figure 4A). This effect was lost when the sFLT-1 e15a was pretreated with heat inactivation. As expected, sFLT-1 i13 was also biologically active. The bioactivity of both sFLT-1 variants appeared comparable.
Akt is an intracellular signal transduction molecule that is phosphorylated with VEGF signaling.16 We found that sFLT-1 e15a blocked VEGF-induced Akt phosphorylation in primary HUVECs (see Figure 4B and 4C). We conclude that sFLT-1 e15a is biologically active and directly antagonizes VEGFR2 signaling, as well as downstream Akt phosphorylation.
sFLT-1 e15a Inhibits Endothelial Cell Migration and Invasion
We next examined whether sFLT-1 e15a inhibits endothelial migration (Figure 5A and 5B) and invasion (Figure 5C and 5D) using the xCELLigence system. This assay measures electric impedance across the wells and has an advantage over end point experiments in that it provides a continuous readout of results in real time. VEGF promoted endothelial cell migration (Figure 5A and 5B) and invasion (Figure 5C and 5D), which was blocked by adding either sFLT-1 e15a or sFLT-1 i13 with VEGF. In contrast, heat-inactivated sFLT-1 e15a did not affect VEGF-induced migration or invasion.
sFLT-1 e15a Inhibits Endothelial Tube Formation
We next examined whether sFLT-1 e15a inhibited endothelial (HUVEC) tube formation on matrigel (Figure 5E and 5F). VEGF promoted endothelial tube formation (quantified as the number of tubules formed) compared with control, and this was blocked by adding sFLT-1 e15a. sFLT-1 e15a alone also significantly disrupted tube formation compared with cells treated with VEGF alone.
sFLT-1 e15a Inhibits Murine Aortic Ring Sprouting
We finally examined that whether sFLT-1 e15a inhibits angiogenesis using a recently described mouse aortic ring sprouting assay (Figure 6A and 6B).15 VEGF significantly promoted aortic ring sprouting (assessed as the average number of sprouts/aortic ring) compared with control. However, the number of VEGF-induced sprouts was significantly reduced by administering sFLT-1 e15a. Recombinant sFLT-1 i13 also significantly reduced the number of aortic ring sprouts compared with VEGF alone.
The evidence implicating sFLT-1 in the pathophysiology of preeclampsia is compelling. First, there is biological plausibility. That sFLT-1 is a known VEGF ligand binding trap (antagonizing the ability of VEGF to promote vascular homeostasis4) is consistent with the fact that endothelial dysfunction is a hallmark of preeclampsia. Mechanistically, adenoviral administration of sFLT-1 to pregnant rats causes hypertension and proteinuria, recapitulating key clinical features of preeclampsia.4,17 There is also kidney endotheliosis in the model,4 a histopathologic finding of glomerular swelling considered pathognomonic for preeclampsia when seen in human kidney biopsies. Finally, women diagnosed with preeclampsia have significantly elevated levels of sFLT-1 that correlate with disease severity, with levels often rising weeks before clinical disease.5
The pathophysiological origin of preeclampsia has been recognized for perhaps >2 millennia as a disease, where the culprit(s) are placentally derived factors. This has arisen from the longstanding clinical observation, which is still evident today—that delivery of the placenta ‘cures’ the disease.
Given all these facts, sFLT-1 e15a—the predominant placentally derived sFLT-1 variant—is likely to be central to the pathophysiology of preeclampsia. Therefore, we set out to characterize sFLT-1 e15a protein given it has remained poorly characterized. Most of the current literature on sFLT-1 detection will have used reagents that indiscriminately detect all sFLT-1 isoforms, including sFLT-1 i13 which is likely to have a significant endothelial source.6
In this study, we have characterized the bioactivity and serum levels of sFLT-1 e15a protein. An important strength of this study is that we performed our functional interrogations using exclusively primary human tissues (with the exceptions that we used BaF3 cell line as a bioassay to examine VEGFR2 cell signaling and that we used mouse aortic rings for a novel ex vivo assay).
By generating a new sFLT-1 e15a ELISA, we have shown that levels increase across gestation and are significantly elevated with preterm preeclampsia (10-fold compared with controls). In this set of samples, serum levels of total sFLT-1 were also significantly increased (measured using the existing commercial ELISA which measures all sFLT-1 variants).
It is possible that an sFLT-1 e15a ELISA, which largely detects placentally-derived sFLT-1, may perform better as a biomarker test than the commercial sFLT-1 ELISA (detects all sFLT-1 variants). The reason is that sFLT-1 i13 is secreted from a variety of sources, notably endothelium. It is therefore possible that serum levels of sFLT-1 i13 are increased in other maternal inflammatory states where there is no preeclampsia, such as obesity and gestational diabetes mellitus. However, the cohort we examined is not suited to examine the relative diagnostic performance of the sFLT-1 e15a ELISA and the commercial sFLT-1 ELISA because preterm preeclampsia is known to have high levels of sFLT-1 relative to controls. As such, both ELISAs detected sFLT-1 e15a and total sFLT-1 at extremely elevated levels. We are undertaking further studies in more appropriate cohorts to compare the performance of the sFLT-1 e15a ELISA to diagnose and predict preeclampsia compared with the commercial sFLT-1 ELISA.
We have confirmed that sFLT-1 e15a protein is bioactive and directly antagonizes VEGF signaling of VEGFR2. Furthermore, we have shown sFLT-1 e15a inhibits endothelial cell migration, invasion, tube formation, and aortic ring sprouting. When considered in light of the fact sFLT-1 e15a is the predominant splice transcript of FLT-1 mRNA in placenta,6 our work suggests that sFLT-1 e15a may be the dominant sFLT-1 splice variant responsible for preeclampsia. It points to the possibility that sFLT-1 e15a is an important molecule centrally involved in the pathogenesis of preeclampsia.
The implication of our work is that those developing therapeutic strategies to decrease sFLT-1 secretion (or inhibit its biological activity) should take into consideration this placentally derived sFLT-1 e15a variant. For example, for drugs designed to decrease placental sFLT-1 production, it may be optimal to specifically show that they decrease placental production of sFLT-1 e15a or block effects of sFLT-1 e15a on endothelial cells. As noted, it is possible that an ELISA that specifically detects placentally derived sFLT-1 e15a may have better diagnostic potential than the commercial sFLT-1 ELISA, although this premise requires proper examination.
We have undertaken studies on the newly described sFLT-1 variant, sFLT-1 e15a. We have confirmed that it is vastly increased in preeclampsia and is bioactive; sFLT-1 e15a antagonized VEGF signaling and inhibited endothelial cell migration, invasion, tube formation, and angiogenic sprouting from aorta ex vivo. Given placentally derived sFLT-1 appears central to preeclamptic pathogenesis, we suggest that the development of therapeutics and diagnostics for preeclampsia should take sFLT-1 e15a into account. Specifically, there may be significant biomarker potential of measuring serum sFLT-1 e15a. It may be important that candidate therapies are shown to also target placental sFLT-1 e15a either by decreasing placental secretion, neutralizing the biological activity of circulating sFLT-1 e15a, or directly antagonizing its antiangiogenic effects at the level of the endothelium.
We wish to thank the research midwives at Mercy Hospital for Women for recruiting women and obtaining clinical samples and to the patients for kindly donating samples. We thank Steven Stacker, Peter MacCallum Cancer Institute, Victoria, and Circadian Technologies (Vegenics Pty Limited, Victoria, Australia) for the kind donation of the Ba/F3 cells. We also thank Dr Sandra Nicholson, Walter and Eliza Hall Institute of Medical Research, for the donation of IL-3 culture media and assistance with protein production.
Sources of Funding
This work was supported by The National Health and Medical Research Council (NHMRC; Project grant #1061977), The Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) Research Foundation Arthur Wilson scholarship (to K.R. Palmer), and The Keith Fitzmaurice Bursary (to K.R. Palmer). The following received salary support from NHMRC: S. Tong (#1050765), T.J. Kaitu’u-Lino (#1062418), N.J. Hannan (#628927), and K.R. Palmer (#607219).
The online-only Data Supplement is available with this article at http://hyper.ahajournals.org/lookup/suppl/doi:10.1161/HYPERTENSIONAHA.115.05883/-/DC1.
- Received May 22, 2015.
- Revision received June 6, 2015.
- Accepted September 3, 2015.
- © 2015 American Heart Association, Inc.
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Novelty and Significance
What Is New?
fms-Like tyrosine kinase-1 (sFLT-1) e15a is the major placentally derived sFLT-1 variant. Given preeclampsia is caused by placental release of sFLT-1, sFLT-1 e15a may be the major variant contributing to preeclampsia.
This is the first description of serum levels of sFLT-1 e15a in preeclampsia, and serum levels across gestation in normal pregnancies.
This report demonstrates that sFLT-1 e15a is bioactive and blocks vascular endothelial growth factor receptor 2 signaling.
This work also shows that sFLT-1 e15a protein is antiangiogenic.
What Is Relevant?
Preeclampsia a major hypertensive disorder of pregnancy, caused by the placental release of sFLT-1.
sFLT-1 e15a protein may be the major sFLT-1 variant contributing to the pathogenesis of preeclampsia.