OBJECTIVE: The objectives of the study were first, to compare different markers of maternal vascular function in women with gestational diabetes mellitus (GDM), preeclampsia (PE), or gestational hypertension (GH) and women whose pregnancies were unaffected by these complications. Second, to assess the association between maternal vascular function and markers of placental perfusion, maternal vascular - placental axis, in these four groups of women.
METHODS: This was a prospective observational study of women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks\' gestation at King\'s College Hospital, London, UK. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, Doppler studies of the uterine arteries and ophthalmic arteries, carotid-femoral pulse-wave velocity (PWV) measurements, estimation of augmentation index (AIx) and total peripheral resistance and measurements of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFLT-1). Linear regression was performed for the outcomes of uterine artery pulsatility index (UtA-PI) multiples of median (MoM), PLGF MoM and sFLT-1 MoM. Ophthalmic artery peak systolic velocity (PSV) ratio, PWV , AIx and total peripheral vascular resistance were assessed as potential predictors. This analysis was carried out in all women and separately in the different groups.
RESULTS: The study population of 6502 women included 614 (9.4%) with GDM, 140 (2.1%) who subsequently developed PE and 129 (2.0%) who developed GH. Women with GDM, compared to those with pregnancies unaffected by GDM, PE or GH, had increased PWV. Women with PE or GH, compared to those with unaffected pregnancies, had lower PlGF MoM and higher UtA-PI MoM, sFLT1 MoM, AIx, PWV, total peripheral resistance and ophthalmic artery PSV ratio. In unaffected pregnancies, ophthalmic artery PSV ratio was predictive of UtA-PI MoM, and ophthalmic artery PSV ratio, AIx, total peripheral resistance, and PWV were predictive of PLGF MoM and sFLT-1 MoM. In women with GDM, ophthalmic artery PSV ratio was predictive of UtA-PI MoM and ophthalmic artery PSV ratio, total peripheral resistance, and PWV were predictive of PLGF MoM, and total peripheral resistance was predictive of sFLT-1 MoM. In women with PE, ophthalmic artery PSV ratio was predictive of UtA-PI MoM, PLGF MoM and sFLT-1 MoM. In women unaffected by GDM, PE or GH, ophthalmic artery PSV ratio was predictive of UtA-PI MoM and AIx, total peripheral resistance, PWV and ophthalmic artery PSV ratio were predictive of PLGF MoM and sFLT-1 MoM.
CONCLUSIONS: In the third trimester of pregnancy, women with PE, GH, and GDM present with increased arterial stiffness. In addition, those diagnosed with hypertensive complications show increased peripheral vascular resistance. Ophthalmic artery PSV ratio provides predictive information for placental perfusion and function for all pregnant women, whereas vascular indices are more informative for placental function in women with unaffected pregnancy and those with GDM, than in those with PE or GH. These data suggest that vascular assessment in women during pregnancy may not only provide information about maternal vascular health but can be used to offer information about individual risk for development of placental insufficiency. The selection of vascular index will have to be tailored according to maternal profile and pregnancy complication.

UNASSIGNED: Circulating angiogenic factors are used for prediction of placenta-related complications, but their associations with first-trimester placental development is unknown. This study investigates associations between maternal angiogenic factors and utero-placental vascular volume (uPVV) and utero-placental vascular skeleton (uPVS) as novel imaging markers of volumetric and morphologic (branching) development of the first-trimester utero-placental vasculature.
METHODS: In 185 ongoing pregnancies from the VIRTUAL Placenta study, a subcohort of the ongoing prospective Rotterdam Periconception cohort, three-dimensional power Doppler ultrasounds of the placenta were obtained at 7-9-11 weeks gestational age (GA). The uPVV was measured as a parameter of volumetric development and reported the vascular quantity in cm3. The uPVS was generated as a parameter of morphologic (branching) development and reported the number of end-, bifurcation- crossing- or vessel points and total vascular length. At 11 weeks GA, maternal serum biomarkers suggested to reflect placental (vascular) development were assessed: placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and soluble endoglin (sEng). sFlt-1/PlGF and sEng/PlGF ratios were calculated. Multivariable linear regression with adjustments was used to estimate associations between serum biomarkers and uPVV and uPVS trajectories.
RESULTS: Serum PlGF was positively associated with uPVV and uPVS development (uPVV: β = 0.39, 95% CI = 0.15;0.64; bifurcation points: β = 4.64, 95% CI = 0.04;9.25; crossing points: β = 4.01, 95% CI = 0.65;7.37; total vascular length: β = 13.33, 95% CI = 3.09;23.58, all p-values < 0.05). sEng/PlGF ratio was negatively associated with uPVV and uPVS development. We observed no associations between sFlt-1, sEng or sFlt-1/PlGF ratio and uPVV and uPVS development.
CONCLUSIONS: Higher first-trimester maternal serum PlGF concentration is associated with increased first-trimester utero-placental vascular development as reflected by uPVV and uPVS. Clinical trial registration number Dutch Trial Register NTR6854.

The etiology of vascular problems in beta-thalassemia has been linked to endothelial damage. Antiangiogenic proteins such as soluble Fms-like tyrosine kinase-1 (sFLT-1) inhibit the signaling of vascular endothelial growth factor and placental growth factor, resulting in a decrease in the development of new blood vessels. Additionally, they promote the maturation of existing blood vessels and lead to endothelial dysfunction. This study aimed to assess the role of sFLT-1 in adult patients with beta-thalassemia major (TM) as a biomarker of endothelial dysfunction and its association with pulmonary hypertension (PHT). A total of 90 subjects were recruited and categorized into two groups: 45 patients with beta-TM, who were further divided based on the presence or absence of PHT, and 45 healthy individuals served as a control group. Serum sFLT-1 was determined using the enzyme-linked immunosorbent assay technique. The results revealed that Beta-TM patients had higher sFLT-1 levels than the control group. In addition, patients with PHT had significantly higher sFLT-1 levels compared to those without PHT. The levels of sFLT-1 were positively correlated with von Willebrand factor, serum ferritin, and high-sensitivity C-reactive protein. Regression analyses demonstrated a significant association between high sFLT-1 levels and the occurrence of PHT. Additionally, sFLT-1 (at a cutoff value of 8.84 pg/mL) demonstrated a sensitivity of 83.30% and a specificity of 80.0% in diagnosing thalassemic patients with PHT. In conclusion, beta-TM patients with elevated serum levels of sFLT-1 are at risk of developing endothelial dysfunction and subsequent development of PHT.

Preeclampsia is characterized by impaired angiogenesis and assessment of angiogenic factors can play a crucial role in the early diagnosis of preeclampsia. The current study reports the levels of angiogenic factors longitudinally from early pregnancy in women with preeclampsia and in the subtypes of preeclampsia, to identify their role in early prediction of preeclampsia. A total of 1154 women with singleton pregnancies were recruited in early pregnancy from 2 hospitals. Blood samples were collected, plasma samples were separated and stored at four time points across gestation: V1 = 11-14 weeks, V2 = 18-22 weeks, V3 = 26-28 weeks, and V4 = at delivery. The current study includes a total of 108 women developed preeclampsia (PE), and 216 matched controls. Angiogenic factors were estimated using commercially available ELISA kits. Receiver operating characteristic (ROC) curves were used to evaluate the potential diagnostic value in the prediction of PE. Lower levels of VEGF, PlGF, and higher levels of sEng and sEng/PlGF ratio (p < 0.05 for all) predate clinical diagnosis in women with preeclampsia. sEng levels and sEng/PlGF ratio showed significant correlation with odds of preeclampsia at all the timepoints. This study identifies a cut off of 33.5 for sFlt-1/PlGF and 25.9 for sEng/PlGF for prediction of early onset preeclampsia. This study reports various angiogenic factors serially across gestation in a general population to identify women at risk of developing preeclampsia and its subtypes. The study also reports a potential biomarker and a pragmatic window for estimation of angiogenic markers to identify women at risk.

BACKGROUND: The aim of the study was to identify predictive values of the soluble fms-like tyrosine kinase/placental growth factor (sFlt-1/PlGF) ratio and interleukin (IL)-6, assessed with a clinically available method in a large-volume biochemistry laboratory, in maternal blood, amniotic fluid, and umbilical cord blood for the presence of the placental lesions consistent with maternal vascular malperfusion (MVM) and acute histological chorioamnionitis (HCA), respectively.
METHODS: This retrospective study included 92 women with preterm labor with intact membranes (PTL) delivered within 7 days of admission with gestational ages between 22+0 and 34+6 weeks. The sFlt-1/PlGF ratio and IL-6 were assessed in stored samples of maternal serum, amniotic fluid, and umbilical cord serum using Elecsys® sFlt-1, PlGF, and IL-6 immunoassays.
RESULTS: Women with MVM had a higher sFlt-1/PlGF ratio in the maternal serum, compared to those without MVM (19.9 vs. 4.6; p < 0.0001), but not in the amniotic fluid or umbilical cord blood. A cut-off value of 8 for the sFlt-1/PlGF ratio in maternal serum was identified as optimal for predicting MVM in patients with PTL. Women with HCA had higher concentrations of IL-6 in maternal serum, compared to those without HCA (11.1 pg/mL vs. 8.4 pg/mL; p = 0.03), amniotic fluid (9,216 pg/mL vs. 1,423 pg/mL; p < 0.0001), and umbilical cord blood (20.7 pg/mL vs. 10.7 pg/mL, p = 0.002). Amniotic-fluid IL-6 showed the highest predictive value. A cut-off value of IL-6 concentration in the amniotic fluid of 5,000 pg/mL was found to be optimal for predicting HCA in PTL.
CONCLUSIONS: Maternal serum sFlt-1/PlGF and amniotic fluid IL-6 concentrations can be used for liquid biopsy to predict placental lesions in women with PTL who deliver within 7 days.

BACKGROUND: Gestational hypertension, often associated with elevated soluble Fms-related receptor tyrosine kinase 1 (sFlt-1), poses significant risks to both maternal and fetal health. Hydrogen sulfide (H2S), a gasotransmitter, has demonstrated blood pressure-lowering effects in hypertensive animals and humans. However, its role in pregnancy-induced hypertension remains unclear.
OBJECTIVE: This study aimed to investigate the impact of GYY4137, a slow-release H2S donor, on sFlt-1-induced hypertension in pregnant rats and examine the underlying mechanisms.
METHODS: Pregnant rats were administered sFlt-1 (6 μg/kg/day, intravenously) or vehicle from gestation day (GD) 12 to 20. A subset of these groups received GYY4137 (an H2S donor, 50 mg/kg/day, subcutaneously) from GD 16 to 20. Serum H2S levels, mean arterial blood pressure (CODA tail-cuff), uterine artery blood flow (ultrasonography), vascular reactivity to vasopressors and endothelial-dependent relaxation (myography), endothelial nitric oxide synthase (eNOS) protein expression in uterine arteries (Western blotting) were assessed. In addition, maternal weight gain, as well as fetal and placental weights, were measured.
RESULTS: Elevated sFlt-1 reduced both maternal weight gain and serum H2S levels. GYY4137 treatment restored both weight gain and H2S levels in sFlt-1 dams. sFlt-1 increased mean arterial pressure and decreased uterine artery blood flow in pregnant rats. However, treatment with GYY4137 normalized blood pressure and restored uterine blood flow in sFlt-1 dams. sFlt-1 dams exhibited heightened vasoconstriction to phenylephrine and GYY4137 significantly mitigated the exaggerated vascular contraction. Notably, sFlt-1 impaired endothelium-dependent relaxation, while GYY4137 attenuated this impairment by upregulating eNOS protein levels and enhancing vasorelaxation in uterine arteries. GYY4137 mitigated sFlt-1-induced fetal growth restriction.
CONCLUSIONS: sFlt-1 mediated hypertension is associated with decreased H2S levels. Replenishing H2S with the donor GYY4137 mitigates hypertension and improves vascular function and fetal growth outcomes. This suggests modulation of H2S could offer a novel therapeutic strategy for managing gestational hypertension and adverse fetal effects.

The present systematic review analyses the role of soluble fms-like tyrosine kinase-1 (sFLT-1) as an indirect biomarker of endothelial dysfunction in sepsis or septic shock from articles published in PubMed between 2010 and March 2022.
A systematic review of studies studying sFLT-1 monitoring in intensive care units in adults with sepsis or septic shock vs. controls for sepsis diagnosis and prognosis has been carried out (PROSPERO CRD42023412929 Registry).
The endothelial dysfunction of sepsis is one of the keys to the development of the disease. VEGF binds to sFLT-1 acting as a competitive inhibitor of VEGF signalling in endothelial cells and thus neutralizes its pro-inflammatory effects. Endothelial dysfunction is reflected in increased sFLT-1 levels. High values of sFLT-1 were used for the differential diagnosis of sepsis versus other inflammatory pathologies, septic shock versus other types of shock, were elevated over time, estimation of disease prognosis, correlation with sepsis severity, organ dysfunction, and mortality prediction.
It is evident that sepsis is based on endothelial dysfunction. sFLT-1 is one of the main biomarkers of microvascular alteration and is a predictive diagnostic and prognostic biomarker.

Preeclampsia is a severe complication of pregnancy, affecting an estimated 4 million women annually. It is one of the leading causes of maternal and fetal mortality worldwide, and it has life-long consequences. The maternal multisystemic symptoms are driven by poor placentation, which causes syncytiotrophoblastic stress and the release of factors into the maternal bloodstream. Amongst them, the soluble fms-like tyrosine kinase-1 (sFLT-1) triggers extensive endothelial dysfunction by acting as a decoy receptor for the vascular endothelial growth factor (VEGF) and the placental growth factor (PGF). Current interventions aim to mitigate hypertension and seizures, but the only definite treatment remains induced delivery. Thus, there is a pressing need for novel therapies to remedy this situation. Notably, CBP-4888, a siRNA drug delivered subcutaneously to knock down sFLT1 expression in the placenta, has recently obtained Fast Track approval from the Food and Drug Administration (FDA) and is undergoing a phase 1 clinical trial. Such advance highlights a growing interest and significant potential in gene therapy to manage preeclampsia. This review summarizes the advances and prospects of gene therapy in treating placental dysfunction and illustrates crucial challenges and considerations for these emerging treatments.

Pre-eclampsia (PE) is a hypertensive disorder of pregnancy which is associated with increased risk of neurodevelopmental disorders in exposed offspring. The pathophysiological mechanisms mediating this relationship are currently unknown, and one potential candidate is the anti-angiogenic factor soluble Fms-like tyrosine kinase 1 (sFlt-1), which is highly elevated in PE. While sFlt-1 can impair angiogenesis via inhibition of VEGFA signalling, it is unclear whether it can directly affect neuronal development independently of its effects on the vasculature. To test this hypothesis, the current study differentiated the human neural progenitor cell (NPC) line ReNcell® VM into a mixed culture of mature neurons and glia, and exposed them to sFlt-1 during development. Outcomes measured were neurite growth, cytotoxicity, mRNA expression of nestin, MBP, GFAP, and βIII-tubulin, and neurosphere differentiation. sFlt-1 induced a significant reduction in neurite growth and this effect was timing- and dose-dependent up to 100 ng/ml, with no effect on cytotoxicity. sFlt-1 (100 ng/ml) also reduced βIII-tubulin mRNA and neuronal differentiation of neurospheres. Undifferentiated NPCs and mature neurons/glia expressed VEGFA and VEGFR-2, required for endogenous autocrine and paracrine VEGFA signalling, while sFlt-1 treatment prevented the neurogenic effects of exogenous VEGFA. Overall, these data provide the first experimental evidence for a direct effect of sFlt-1 on neurite growth and neuronal differentiation in human neurons through inhibition of VEGFA signalling, clarifying our understanding of the potential role of sFlt-1 as a mechanism by which PE can affect neuronal development.

Preeclampsia, a serious complication of pregnancy, involves intricate molecular and cellular mechanisms. Fetal microchimerism, where fetal cells persist within maternal tissues and in circulation, acts as a mechanistic link between placental dysfunction and maternal complications in the two-stage model of preeclampsia. Hormones, complements, and cytokines play pivotal roles in the pathophysiology, influencing immune responses, arterial remodeling, and endothelial function. Also, soluble HLA-G, involved in maternal-fetal immune tolerance, is reduced in preeclampsia. Hypoxia-inducible factor 1-alpha (Hif-α) dysregulation leads to placental abnormalities and preeclampsia-like symptoms. Alterations in matrix metalloproteinases (MMPs), endothelins (ETs), chemokines, and cytokines contribute to defective trophoblast invasion, endothelial dysfunction, and inflammation. Preeclampsia\'s genetic complexity includes circRNAs, miRNAs, and lncRNAs. CircRNA_06354 is linked to early-onset preeclampsia by influencing trophoblast invasion via the hsa-miR-92a-3p/VEGF-A pathway. The dysregulation of C19MC, especially miR-519d and miR-517-5p, affects trophoblast function. Additionally, lncRNAs like IGFBP1 and EGFR-AS1, along with protein-coding genes, impact trophoblast regulation and angiogenesis, influencing both preeclampsia and fetal growth. Besides aberrations in CD31+ cells, other potential biomarkers such as MMPs, soluble HLA-G, and hCG hold promise for predicting preeclampsia and its complications. Therapeutic interventions targeting factors such as peroxisome PPAR-γ and endothelin receptors show potential in mitigating preeclampsia-related complications. In conclusion, preeclampsia is a complex disorder with a multifactorial etiology and pathogenesis. Fetal microchimerism, hormones, complements, and cytokines contribute to placental and endothelial dysfunction with inflammation. Identifying novel biomarkers and therapeutic targets offers promise for early diagnosis and effective management, ultimately reducing maternal and fetal morbidity and mortality. However, further research is warranted to translate these findings into clinical practice and enhance outcomes for at-risk women.