Placenta Growth Factor Levels Research Articles

Serum and Vitreous Levels of Placenta Growth Factor in Diabetic Retinopathy Patients: Correlation With Disease Severity and Optical Coherence Tomographic Parameters.

Purpose The primary objective of this study was to compare placenta growth factor (PlGF) levels in the serum and vitreous of diabetic retinopathy (DR) patients to non-diabetic controls. Additionally, the study aimed to establish associations between serum and vitreous PlGF concentrations and to examine the correlation between vitreous PlGF in DR patients and morphological parameters. Methods This study included serum and vitreous samples from 38 patients, including 21 patients with DR and 17 non-diabetic controls. The control group included non-diabetic patients with rhegmatogenous retinal detachment with retinal tears secondary to posterior vitreous detachment or trauma. PlGF levels were quantified in vitreous and serum samples using an enzyme-linked immunosorbent assay (ELISA). Optical coherence tomography (OCT) scans from DR patients were evaluated to measure the central retinal thickness (CRT) and macular volume (MV). Results DR patients had significantly higher mean vitreous PlGF levels compared to non-DR patients (70.0±39.2 vs. 46.47±9.7 pg/mL, p-value=0.004). However, no significant increase in mean serum PlGF levels was observed in DR patients (p-value=0.232). Within the DR group, proliferative DR (PDR) patients presented significantly higher vitreous PlGF levels than non-PDR (NPDR) patients (76.5±41.0 vs. 42.5±5.0 pg/mL, p-value=0.009). There was no association between serum and vitreous PlGF levels. The correlation between vitreous PlGF levels and morphological parameters was rsp=0.175, p-value=0.488 for CRT, and rsp=0.288, p-value=0.262 for MV. Conclusion This study emphasizes the important role of PlGF in neovascularization, specifically highlighting its overexpression exclusively in vitreous from PDR patients. The observed increase in PlGF levels may be indicative of disease severity. The lack of correlation between vitreous and serum PlGF levels suggests a potential dissociation between intravitreal and systemic PlGF synthesis. Consequently, targeting PlGF in therapeutic approaches may offer an additional strategy for ocular pathologies with a neovascular component.

Comparison of circulating maternal placenta growth factor levels and sonographic evaluation of patients with abnormal first trimester screening analytes.

To evaluate the role of mid-trimester placental growth factor (PlGF) in patients with abnormal circulating levels of first-trimester biomarkers. Retrospective cohort study including singleton pregnancies complicated by abnormal first-trimester biomarkers (2017-2020). Pregnancies complicated with chromosomal/structural anomalies were excluded. All patients had ultrasound imaging including uterine artery Doppler combined with measurement of maternal circulating PlGF. Sonographic findings, maternal and perinatal outcomes, and placental histopathology were compared between pregnancies with normal and low (<10th percentile for gestational age) PlGF levels. The diagnostic accuracy of PlGF for the prediction of specific placental-mediated complications was compared with the uterine artery Doppler assessment and additional sonographic findings. Seventy-one pregnancies were assessed, of which 35 (49.3%) had low PlGF levels. Maternal sociodemographic characteristics, nulliparity, and aspirin consumption were comparable. In comparison with patients with normal PlGF levels, individuals with low PlGF levels had a higher rate of fetal growth restriction (EFW <3rd centile; 42.9% vs. 8.3%, p=0.001), preterm-preeclampsia (22.9% vs. 0%, p=0.002), preterm delivery <34weeks (54.3% vs. 8.3%, p<0.001) and maternal vascular malperfusion placental pathology (72.7% vs. 21.7%, p<0.001) following delivery. Adjusting for uterine artery Doppler and fetal biometry status, mid-trimester low PlGF remained significantly associated with these placental-mediated complications. The predictive capacity of PlGF outperformed ultrasound imaging with only minimal diagnostic improvement when ultrasound information was combined with PlGF status. In pregnancies with unexplained abnormal first-trimester biomarkers, mid-trimester PlGF outperformed a comprehensive ultrasound assessment in the identification of a subset of patients destined to develop placental dysfunction. This blood test may be an alternative initial approach in this context, especially where access to specialist care is more geographically challenging.

Increased Placental sFLT1 (Soluble fms-Like Tyrosine Kinase Receptor-1) Drives the Antiangiogenic Profile of Maternal Serum Preceding Preeclampsia but Not Fetal Growth Restriction.

Preeclampsia and fetal growth restriction (FGR) are both associated with an increased ratio of sFLT1 (soluble fms-like tyrosine kinase-1) to PlGF (placenta growth factor) in maternal serum. In preeclampsia, it is assumed that increased placental release of sFLT1 results in PlGF being bound and inactivated. However, direct evidence for this model is incomplete, and it is unclear whether the same applies in FGR. We conducted a prospective cohort study where we followed 4212 women having first pregnancies from their dating ultrasound, obtained blood samples serially through the pregnancy, and performed systematic sampling of the placenta after delivery. The aim of the present study was to determine the relationship between protein levels of sFLT1 and PlGF in maternal serum measured at ≈36 weeks and placental tissue lysates obtained after term delivery in 82 women with preeclampsia, 50 women with FGR, and 132 controls. The sFLT1:PlGF ratio was increased in both preeclampsia and FGR in both the placenta and maternal serum. However, in preeclampsia, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental sFLT1 level (r=0.45; P<0.0001) but not placental PlGF level (r=-0.17; P=0.16). In contrast, in FGR, the maternal serum ratio of sFLT1:PlGF was strongly associated with placental PlGF level (r=-0.35; P=0.02) but not sFLT1 level (r=0.04; P=0.81). We conclude that the elevated sFLT1:PlGF ratio is primarily driven by increased placental sFLT1 in preeclampsia, whereas in FGR, it is primarily driven by decreased placental PlGF.

The Association Between Maternal Placenta Growth Factor Levels and Small-for-Gestational Age Infants: Findings From the Multi-Country Women First Study

ObjectivesExamine the association between Placenta Growth Factor (PlGF) levels during pregnancy, maternal nutrition supplementation (MNS) and the prevalence of small-for-gestational age (SGA) infants in the Women First (WF) Study.MethodsWF is a RCT of MNS consisting of a lipid-based micronutrient supplement ± a protein-energy supplement (for low maternal BMI or weight gain), provided to women daily until delivery starting either ≥ 3 months pre-conception (Arm 1), at the end of the first trimester (Arm 2) or not at all (control group, Arm 3). Serum samples were obtained at 12 (Arms 1 and 2) and 34 weeks (Arms 1, 2 and 3) gestation from a subset of women in three of the WF sites (Guatemala [Guat] (n = 257); India [Ind] (n = 171, Arms 1 & 2 only); and Pakistan [Pak](n = 279)). PlGF was measured using an ELISA. An ultrasound late in the 1st trimester determined whether infants were SGA at birth (weight-for-age centile < 10, INTERGROWTH-21st standards). PlGF levels were examined for arm, site and time point differences using ANOVA and post-hoc Tukey testing. The association between SGA and PlGF was analyzed by logistic regression adjusting for maternal height, age and education (STATA software v. 17.0).ResultsIn participants with PlGF measurements, the prevalence of SGA infants is 23% in Guat, 44% in Ind and 34% in Pak. PlGF levels increased from 12 to 34 weeks gestation in Arms 1 and 2 in every site (Tukey's adjusted P < 0.0001). There are no differences in PlGF among sites at 12 weeks, whereas all sites are different at 34 weeks (Tukey's adjusted P < 0.0001). Regarding the association between SGA and PlGF (adjusting for maternal height, age and education), there are no differences by arm within each time point and site (arms were combined in subsequent analyses). PlGF is associated with SGA only in Guat at 34 weeks: odds of an infant being SGA decreases as PlGF increases (OR = 0.9989, 95% CI: 0.9981, 0.9998, unadjusted p = 0.015). For a 50 pg/mL increase in PlGF, the odds of the infant being SGA decreased by 0.948 (5.2%; OR 95% CI: 0.909, 0.990).ConclusionsAn association between PlGF and prevalence of SGA was found in Guatemala at 34 weeks: as PlGF increases, the odds of a SGA infant decreases. The MNS did not result in differences among arms.Funding SourcesBill & Melinda Gates Foundation, Eunice Kennedy Shriver NICHD and NIH ODS.

Oxidative stress biomarkers in fetal growth restriction with and without preeclampsia.

Oxidative stress as observed in fetal growth restriction (FGR) and preeclampsia (PE) can be identified by decreased levels of systemic free thiols (FT) and increased levels of plasma ischemia-modified albumin (IMA), which may serve as biomarkers in maternal blood for pregnancy complications. We evaluate the performance of oxidative stress-associated potential biomarkers for FGR and PE, and their relationship with clinical characteristics. A prospective clinical pilot study was performed in healthy controls and women with pregnancies complicated by severe FGR with or without PE. Blood samples were taken directly after inclusion and analyzed for FT; IMA; soluble FMS-like tyrosine kinase-1 (sFlt-1); placenta growth factor (PlGF); and biomarkers like leptin and soluble receptors for advanced glycation end products (sRAGE). Placentas were examined microscopically. Descriptive statistics and receiver operating characteristics statistics were performed. Mothers with both severe FGR and PE had significantly reduced FT levels (p<0.001) and PlGF levels (p<0.001), and increased levels of plasma IMA (p<0.05), sFlt (p<0.001), leptin (p<0.05) and sRAGE (p<0.01) compared to women with FGR only. Systemic FT levels were significantly inversely associated with blood pressure (p<0.01) and plasma IMA (p<0.001), leptin (p=0.01) and sRAGE (p<0.001). Systemic FT and leptin showed significant discriminative ability to differentiate mothers with both FGR and PE from mothers with uncomplicated pregnancies or pregnancies complicated by FGR only. There is a significant discriminative capacity of FT, IMA, leptin and sRAGE that harbor potential as biomarkers of pregnancies complicated by combined FGR and PE.

Predictive value of vascular endothelial growth factor and placenta growth factor for placenta accreta spectrum

This study aimed to assess the maternal features, Vascular Endothelial Growth Factor (VEGF) and Placenta Growth Factor (PLGF) in the Placenta Accreta Spectrum (PAS); then, to determine a predictive value of VEGF and PLGF in the PAS. This prospective case-control study was conducted on 90 pregnant women including 45 PAS, and 45 Normal Placenta (NP). Maternal age, gravidity, C/S, and serum levels of VEGF and PLGF were assessed between NP and PAS, and among NP and PAS sub-groups, including Placenta Accreta (PA), Placenta Increta (PI), and Placenta Percreta (PP). The Multi-gravidity, previous C/S, maternal age, and serum level of PLGF were significantly higher in the PAS group compared to the NP group OR = 42, 8.1, 1.17, and 1.002 (p-value <.05 for all); however, there was no difference regarding serum level of VEGF (p-value >.05). The same differences were seen among NP with PA, PI, and PP sub-groups (p-value <.05 for all, but p-value >.05 for VEGF). Placenta Previa was uniformly distributed across the PAS sub-groups (p-value >.05), also the VEGF and PLGF serum levels did not differ between PAS with Previa and PAS without Previa groups (p-value >.05). A valid cut-off point for PLGF was reported at 63.55. A predictive value of PLGF for the PAS patients is presented enjoying high accuracy and generalisability for the study population. Impact statement What is already known on this subject? The Placenta Accreta Spectrum (PAS), in which the placenta grows too deep in the uterine wall, is responsible for maternal-foetal morbidity and mortality worldwide; so, the antenatal diagnosis of PAS is an important key to improve maternal-foetal health. Normal placental implantation requires a fine balance among the levels of angiogenic and anti-angiogenic factors, such as the Placenta Growth Factor (PLGF), the Vascular Endothelial Growth Factor (VEGF), and soluble Fms-like tyrosine kinase-1. However, there is still controversy regarding The PLGF and VEGF level changes in PAS patients. What do the results of this study add? Despite traditional measuring the levels of PLGF and VEGF from the placenta at the time of delivery; in this study including 90 participants (28–34 weeks of gestation) the maternal serum levels of PLGF and VEGF were measured in advance (temporality causation), resulted in presenting a more valid cut-off point for PLGF in PAS group. In addition, the serum level of PLGF was significantly higher in the PAS and PAS sub-groups compared to the Normal Placenta group. Also, the Previa status of PAS patients did not affect the VEGF and PLGF serum levels. What are the implications of these findings for clinical practice and/or further research? PLGF cut-off point derived from the maternal serum level could predict PAS validly and, if used as a screening test in an earlier pregnancy, the maternal-foetal morbidity and mortality would decrease.

Monitoring intraocular proangiogenic and profibrotic cytokines within 7 days after adjunctive anti-vascular endothelial growth factor therapy for proliferative diabetic retinopathy.

To monitor the intraocular proangiogenic and profibrotic cytokine profiles within 7 days after intravitreous injection of conbercept (IVC) for patients with proliferative diabetic retinopathy (PDR). This prospective, randomized controlled, consecutive, comparativestudy included 157 eyes with PDR. Participant eyes underwent shamIVC or IVC and subsequent vitrectomy at days 2, 3, 4, 5, 6, 7 postinjection. Theintraocular cytokines profiles were measured using beaded assay methods. After IVC, the vascular endothelial growth factor (VEGF)-A level in PDR vitreous decreased rapidly by approximately 10 times at day 2 (p = 0.00001) and kept at a low level at days 3, 4, 5, 6, 7 (p < 0.001, each compared with IVC-sham group). Similar tendency of the change in VEGF-A was observed in aqueous humour. The level of placenta growth factor (PIGF) in aqueous humour decreased 2 days after IVC whereas returned to baseline level after 5 days. The vitreous profibrotic cytokines, tissue growth factor (TGF)-β1, TGF-β2, TGF-β3 and connective tissue growth factor did not increase after IVC in each group. We observed a remarkable and rapid decrease in intraocular VEGF-A, temporal decrease in PIGF from day 2 to day 4, increase in VEGF-C and VEGF-D from day 2 onwards, but no profibrotic switch in PDR eyes after IVC. The findings might suggest that ideal vitrectomy timing might be around 3 days after IVC.

Airway Hyper-Responsiveness Associated With Sickle Cell Disease Is Mediated By Placenta Growth Factor

Airway hyper-responsiveness (AHR) affects about 55-77% of children with sickle cell disease (SCD) and is a risk factor for asthma, increasing the risk of vaso-occlusive events and acute chest syndrome in this patient population. Although in the non-SCD pediatric population AHR is associated with an active allergic response, the molecular mechanisms underlying the high incidence of AHR in a red blood cell disorder remain unclear. Our laboratory has reported that placenta growth factor (PlGF), an erythroid cell secreted-growth factor belonging to the vascular endothelial growth factor family is found at high levels in patients with SCD, mediates increased 5-lipoxygenase (5LO) expression in vitro (Patel et al, 2009). 5LO is the key enzyme in the leukotriene synthetic pathway (LT) and LT levels have been reported to be elevated in SCD (Setty et al, 2002; Jennings et al, 2008). We hypothesized that PlGF contributes to AHR in SCD and investigated the direct contribution of PlGF to AHR in mice with genetically imposed deficiency of PlGF and in the well characterized Berkeley sickle mouse model (HbS mice). We have previously reported that imposing PlGF deficit in HbS mice resulted in extremely small litters and the rare HbS/PlGF-/- mice born were infertile (Patel et al, 2010). Hence the PlGF deficient and HbS mice were studied separately. We utilized a well-established murine model of allergen induced AHR using the highly AHR susceptible mouse strain (BALB/c), that either had normal levels of PlGF (PlGFWT) or had a genetically imposed deficit of PlGF (PlGF-/- mice). Results were validated in HbS mice by using pharmacological blockade of this mechanistic pathway. Following allergen treatment with either IL-13 or house dust mites, mice were subjected to a cholinergic challenge and AHR was assessed using either APTI or airway resistance, using an established AHR protocol. Upon allergen challenge, PlGF-/- BALB/c mice showed significantly blunted AHR compared to PlGFWT BALB/c mice: the airway resistance was 683 ± 93.5 vs 1283 ± 229 cm2xs; p≤0.04. PlGF neutralization with a blocking antibody (kindly provided by Thrombogenics, Inc.) reduced the severity of AHR in PlGFWT mice to levels similar to PlGF-/- mice. Consistent with the importance of eosinophils in driving AHR development, bronchoalveolar lavage fluid (BALF) from PlGF-/- mice revealed reduced eosinophils (9.3 ± 6.4 x104 vs. 27.5 ± 4.8 x 104 cell/ml P≤0.05), and decreased leukocyte infiltration of lungs by histology. Mechanistically, PlGF deficiency was associated with decreased 5LO expression in lungs both at the mRNA and protein level. We also found that in addition to 5LO, genetically imposed deficiency of PlGF or its pharmacological inhibition were associated with a 2.5-5 fold decrease in IL17A expression in CD4+ lymphocytes from BALF. AHR susceptibility across mouse strains varies tremendously, and has been reported to be mediated via IL-13 and IL-17A (Lajoie and Wills Karp, Nature Immunology, 2010). The HbS mice were originally outbred and have been crossed to C57Bl/6 mice for six generations. To study AHR in HbS mice while eliminating confounding variables attributable to genetic background difference, we transplanted sickle hematopoietic stem cells from HbS donors into Bl/6 (BoyJ) mice, and derived HbS/Bl/6 chimeric mice that had donor derived sickle hematopoiesis replaced the normal recipient hematopoiesis. C57Bl/6 mice transplanted into congenic BoyJ (Bl/6) mice served as controls. Four months after transplant when the mice were totally chimeric, allergen challenge revealed significant increased AHR in HbS/Bl/6 mice compared to C57/Bl/6 mice. Interestingly, IL17A levels were similar between HbS/Bl/6 and C57/Bl/6mice; whereas they were significantly lower in HbS mice compared to control C57/Bl6 mice prior transplant. Consistent with the role of PlGF in AHR in SCD, PlGF neutralizing antibody reduced the AHR severity in chimeric HbS/Bl/6 mice; and pharmacological blockade of 5-LO using zileuton, a 5-LO inhibitor significantly decreased the severity of AHR in HbS/Bl/6 mice in comparison to vehicle treated HbS/Bl/6 mice. Overall, our results indicate that PlGF expression exacerbates AHR via regulating the leukotriene and IL-17A pathways. Leukotriene antagonists are licensed for asthma and PlGF antibody is in clinical trials for cancer. These can be used to reduce the pulmonary morbidity in susceptible patients with moderate to severe SCD. Disclosures:No relevant conflicts of interest to declare.

The clinical value of platelet parameters combined with sFlt-1/PlGF in predicting preeclampsia

The aim of this study is to evaluate the association between platelet parameters and soluble vascular endothelial growth factor receptor-1 (sFlt-1)/placenta growth factor (PlGF) in preeclampsia (PE) and establish a prediction model by analyzing commonly used biochemical markers. A nested case-control study involving 270 pregnant women in their second trimester from the Beijing Jishuitan Hospital was conducted. They were divided into PE group and control group. The levels of PlGF, sFlt-1, sFlt-1/PlGF, and platelet parameters were recorded and compared at 20-24 gestational weeks. The correlation between platelet parameters and PlGF, sFlt-1, and sFlt-1/PLGF was then analyzed. A receiver operating characteristic (ROC) curve was used to calculate the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of various biomarkers in predicting PE. In PE group, the levels of mean platelet volume (MPV), platelet distribution width (PDW), sFlt-1, and sFlt-1/PLGF were higher than in the control group, while the levels of platelet count (PC), PC/MPV, and PLGF in PE group were lower. Spearman correlation analysis showed that PC and PC/MPV were negatively correlated with sFlt-1 and sFlt-1/PLGF, and positively correlated with PLGF, while further analysis found that PC/MPV had the largest area under the ROC curve with sensitivity of 83.7% and specificity of 86.2%. The area under curve (AUC) of sFlt-1, PLGF, and sFlt-1/PLGF for predicting PE were 0.731, 0.772, and 0.825, respectively. Their AUCs could be improved to 0.820, 0.838, and 0.873 when combined with PC/MPV. The accuracy of sFlt-1/PlGF in predicting the risk of PE in the second trimester is significantly improved when combined with PC/MPV, which is expected to be an ideal tool for PE prediction.

Clinical Implications

HomeHypertensionVol. 78, No. 1Clinical Implications Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessIn BriefPDF/EPUBClinical Implications Renata Gil Renata GilRenata Gil https://orcid.org/0000-0001-9611-1597 Search for more papers by this author Originally published9 Jun 2021https://doi.org/10.1161/HYPERTENSIONAHA.121.17551Hypertension. 2021;78:3is related toIn Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated MechanismInduction of the PPARγ (Peroxisome Proliferator-Activated Receptor γ)-GCM1 (Glial Cell Missing 1) Syncytialization Axis Reduces sFLT1 (Soluble fms-Like Tyrosine Kinase 1) in the Preeclamptic PlacentaOccupational Physical Activity and New-Onset Hypertension: A Nationwide Cohort Study in ChinaOccupational Activity and New-Onset Hypertension (page 220)Download figureDownload PowerPointThe nature of occupational physical activity (OPA) is vastly different (low intensity, long duration, highly repetitive, or done in a static posture) from the types of physical activity that is recommended by health guidelines. Furthermore, that OPA could be potentially detrimental for health is of great public health importance and warrants further investigation. However, to date, the association between the risk of hypertension and OPA remains uncertain. Using data from the China Health and Nutrition Survey, we first demonstrated that there was an L-shaped association between the OPA and new-onset hypertension in men and a U-shaped association in women. OPA was categorized based on a 40-hour work as <2 (light), 2 to 4 (light to moderate), 4 to 6 (moderate to heavy), and ≥6 (heavy) metabolic equivalent task values, that is, <80, 80 to <160, 160 to <240, and ≥240 metabolic equivalent task hours per week. In men, the risk of new-onset hypertension was significantly increased only among participants with OPA <80 metabolic equivalent task hours per week; however, in women, the lowest risk of new-onset hypertension was found among those with OPA 80 to 240 metabolic equivalent task hours per week. In summary, moderate OPA, in terms of both duration and intensity, is associated with a lower risk of new-onset hypertension among both sexes, whereas heavy OPA was related to increased risk of new-onset hypertension in women only. Our findings suggest that considering OPA might be relevant in the primary prevention of hypertension.Modulation of the AT2R by Estrogen in Aged Females (page 128)Download figureDownload PowerPointThe risk of developing hypertension increases with age. This is particularly true in women after menopause, when blood pressure rises more steeply than in men. Seventy percent of women aged 60 to 70 years are hypertensive, and this rises to 80% after the age of 75 years. Estrogen has protective actions in premenopausal women, but controversy exists around whether hormone replacement therapy is cardioprotective. Currently, hormone replacement therapy is not recommended for the prevention of hypertension. Continued work is needed to fully understand how estrogen affects the cardiovascular system and blood pressure regulation, to disentangle its beneficial and adverse effects. The present study examined the impact of estrogen replacement in aged mice that had recently entered reproductive senescence. The ability of the prohypertensive hormone, angiotensin II, to increase blood pressure was enhanced in aged compared with adult mice. Estrogen replacement reduced the pressor response in aged females, in association with a marked increase in renal AT2 (angiotensin type 2) receptor expression. Furthermore, this beneficial action of estrogen in aged mice was prevented by AT2 receptor blockade. The AT2 receptor is expressed on the X chromosome, and evidence suggests that the AT2 receptor has an enhanced role in premenopausal women, particularly in the kidney. Clinically, the ability of estrogen to increase AT2 receptor expression could provide a pathway via which hormone replacement therapy may exert cardioprotective effects. More importantly, this work suggests it may be possible to bypass the need for hormone replacement therapy, to provide continued protection in women as they age by direct manipulation of the AT2 receptor.Modulation of sFLT1 by the PPARγ-GCM1 Axis (page 230)Download figureDownload PowerPointIatrogenic preterm delivery for severe preeclampsia is a frustrating decision for clinicians to make in 2021. Despite antihypertensive therapies, this disease progressively damages crucial maternal organs and the coagulation system. An endocrine link between the underlying placental disease and multiorgan injury is now understood. Chronic ischemia in the early second trimester inhibits the developing placenta from making protective PlGF (placenta growth factor) and causes it to secrete excessive sFLT1 (soluble fms-like tyrosine kinase 1), which inhibits systemic vasorelaxation via local VEGF (vascular endothelial growth factor). Pharmacological approaches that either rescue PlGF production or repress overexpression of sFLT1 offer a novel alternative to delivery. Here, we present molecular data demonstrating that activation of PPARγ (peroxisome proliferator-activated receptor gamma) signaling within explanted villi from women with severe preeclampsia restores GCM1 (glial cell missing 1)-mediated physiological syncytialization. This in turn represses excessive sFLT1 secretion. We achieved this effect using the PPARγ agonist rosiglitazone—a drug commonly used in diabetes care. Our findings create an opportunity to test the hypothesis that a drug intervention designed to restore normal trophoblast development could effectively reverse the core pathogenesis of severe preeclampsia. Logically, this should be tested in the highest risk women—those with low circulating PlGF levels and abnormal uterine artery Doppler at a 20- to 22-week gestation. A strategy of pharmacological normalization of an abnormal circulating angiogenic profile before the development of hypertension may at last offer an elegant intervention that is of greater value than preterm birth by cesarean due to maternal ill health and hypertension. Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesIn Aged Females, the Enhanced Pressor Response to Angiotensin II Is Attenuated By Estrogen Replacement via an Angiotensin Type 2 Receptor-Mediated MechanismGiannie Barsha, et al. Hypertension. 2021;78:128-137Induction of the PPARγ (Peroxisome Proliferator-Activated Receptor γ)-GCM1 (Glial Cell Missing 1) Syncytialization Axis Reduces sFLT1 (Soluble fms-Like Tyrosine Kinase 1) in the Preeclamptic PlacentaBrooke Armistead, et al. Hypertension. 2021;78:230-240Occupational Physical Activity and New-Onset Hypertension: A Nationwide Cohort Study in ChinaQinqin Li, et al. Hypertension. 2021;78:220-229 July 2021Vol 78, Issue 1Article InformationMetrics Download: 380 © 2021 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.121.17551 Originally publishedJune 9, 2021 PDF download

Heme Regulates the Expression in Erythroblasts of Placenta Growth Factor, a Contributor to Pulmonary Hypertension in Sickle Cell Disease, through the Oxidant Response Transcription Factor NRF2

Patients with sickle cell disease (SCD) have elevated plasma levels of placenta growth factor (PGF), which promotes expression of the pulmonary vasoconstrictor endothelin-1 (ET-1) contributing to pulmonary hypertension, an important age-related and life-limiting complication of SCD. In SCD patients, markers of high iron burden are associated with the highest PGF levels, leading us to the investigation of a mechanism where excessive heme induces PGF expression. Our lab's published work has demonstrated a significant heme-bound iron (hemin) stimulation of the PGF promoter in human K562 cells and in primary human erythroid cells. Our initial experiments with N-acetylcysteine and the nonspecific oxidant hydrogen peroxide, suggested to us a role of oxidant stress in PGF regulation, hypothetically through the NRF2 antioxidant response mechanism.We conducted gene expression analysis by quantitative real time PCR for PGF in human K562 erythroblastoid cells, erythroid-differentiated human and mouse primary bone marrow cells before and after exposure to hemin. We tested the effect of Nrf2 agonists and an antagonist. We analyzed expression of heme oxygenase-1 as a positive control, and expression of several Nrf2 family members, as well as baseline genes. We performed siRNA gene knockdown experiments in cultured cells, chromatin immunoprecipitation experiments and intravenous injection of hemin (120 μmol/kg) in the tail veins of wild type and Nrf2 null mice, followed by assay of plasma PGF by ELISA and qPCR of bone marrow.We find that heme regulates the expression of several members of the Nrf2 family, which in turn may appear to affect PGF expression. More specifically, the antioxidant transcription factory family members NRF2, MafF, MafG and BACH1 are transcriptionally activated in a specific temporal pattern after heme exposure. NFE2 and MafK transcripts were simultaneously repressed by heme treatment. The well-characterized non-oxidative NRF2 agonist sulforaphane activated the endogenous PGF promoter and the NRF2 inhibitor brusatol inhibited heme induction of the endogenous PGF promoter. Specific gene knockdown results using siRNA supports additive roles for NRF2 and its heterodimeric partner MafG in activating the PGF promoter in response to heme, presumably as a heterodimer. We verified direct binding of NRF2 on the PGF promoter by chromatin immunoprecipitation experiments. While PGF regulation shows quite many common aspects to HO-1 regulation (heme and oxidative stress response), we find that protoporphyrin induces HO-1 (known to require BACH-1), but not PGF.In addition to the experimental data from our human K562 cell culture models, we have found corroborating results in primary erythroid-differentiated human and murine hematopoietic cells. In vivo, intravenous injection of heme in wild type mice produces robust secretion of PGF protein into plasma within 3 hours (192 ± 16 vs. 527 ± 62 pg/mL, P <0.0001, mean ± SEM, one-way ANOVA with Sidak's multiple comparison test) and this heme induction of plasma PGF protein is blunted in the Nrf2 null mice (527 ± 62 vs. 343 ± 21 pg/mL, P=0.004).Our results support a mechanism in which accelerated heme exposure in SCD promotes robust expression of PGF in erythroblasts during erythroid differentiation, through a pathway that involves EKLF, NRF2 and MafG, culminating in expression of the vascoconstrictor endothelin-1. This mechanism helps to explain the clinical observation that adults with SCD heavily exposed to red cell transfusion are more likely to develop high endothelin levels and pulmonary hypertension, as a potential consequence of excess heme trafficking from the turnover of transfused red cells. These results might inspire greater adherence to existing approved therapies to chelate iron in SCD. [Display omitted] DisclosuresOfori-Acquah:NuvOx Pharma: Patents & Royalties. Kato:Bayer: Research Funding; Global Blood Therapeutics: Consultancy; MAST Therapeutics: Research Funding; Novartis: Consultancy.

Nested Case-Control Study of Corin Combined with sFlt-1/PLGF in Predicting the Risk of Preeclampsia.

BackgroundPreeclampsia (PE), a serious pregnancy disorder, is responsible for maternal and fetal mortality worldwide. At present, numerous candidate biomarkers have been studied to predict PE.ObjectiveTo explore the role of Corin in PE risk prediction and then evaluate the predictive ability of soluble vascular endothelial growth factor receptor-1 (sFlt-1), placenta growth factor (PLGF), and sFlt-1/PLGF after the addition of Corin.MethodsA total of 135 pregnant women from Affiliated Hospital of Shandong University of Traditional Chinese Medicine participated in this study in their first trimester. A nested case–control study was conducted and all subjects were divided into PE groups (n=46) and controls (n=89). The levels of PLGF, sFlt-1, sFlt-1/PLGF ratio, and Corin of the two groups at 12–16 weeks of gestation were measured and analyzed. Receiver operating characteristic (ROC) curve, net reclassification index (NRI) and integrated discrimination index (IDI) were calculated to evaluate the predictive ability of various biomarkers.ResultsThe concentrations of sFlt-1, sFlt-1/PLGF, and Corin in PE group were significantly higher than that in controls, while the concentration of PLGF in the PE group was lower. The area under curve (AUC) of sFlt-1, PLGF and sFlt-1/PLGF for predicting PE was 0.786, 0.719 and 0.866, respectively. Combined with Corin, the prediction ability of the above biomarkers could be improved to 0.876, 0.847, and 0.897, respectively. Corin in combination with sFlt-1/PLGF resulted in improvements with 12.6% being reclassified and a resulting NRI of 0.142 (0.020~0.263) and IDI of 0.087 (0.037~0.137).ConclusionThe addition of Corin to sFlt-1, PLGF and sFlt-1/PLGF can improve the ability of each marker to predict PE risk. Corin in combination with sFlt-1/PLGF can be used as ideal markers to identify the pregnant women who subsequently develop PE, which will help in risk stratification and better therapeutic management.

Endostatin and Vascular Endothelial Growth Factor-A165b May Contribute to Classification of Pulmonary Hypertension.

Background: Pulmonary hypertension (PH) is characterized by dysregulation of small pulmonary arteries. In addition to endostatin (ES), placenta growth factor (PlGF), vascular endothelial growth factor-A (VEGF-A), and the anti-angiogenesis isoform of VEGF-A (VEGF-A165b) are associated with PH. However, the usefulness of these biomarkers in PH in unknown. We investigated whether these 4 biomarkers are related to PH classification.Methods and Results: Between July 2015 and August 2017, 33 control patients and 107 PH patients were enrolled in the study. Among the PH patients, 48 had pulmonary arterial hypertension (PAH), 5 had left heart disease-associated PH (LHD-PH), 4 had lung disease-associated PH (LD-PH), and 50 had chronic thromboembolic PH (CTEPH). Among the PAH patients, 16 had idiopathic PAH (IPAH) and 17 had connective tissue disease-associated PAH (CTD-PAH). PlGF, total VEGF-A, and VEGF-A165b levels were measured in the control and PH groups. ES was only measured in the PH group. VEGF-A165b levels were significantly higher in the LD-PH group than in the PAH, LHD-PH, and CTEPH groups (all P<0.001). PlGF levels were significantly higher in the CTD-PAH group than in the IPAH and control groups. ES levels were significantly correlated with the 6-min walk distance (P<0.001), B-type natriuretic peptide (P<0.001), and pulmonary vascular resistance (P=0.008).Conclusions: ES could detect CTD-PAH in PAH and may be an indicator of PH severity. VEGF-A165b was useful in detecting LD-PH.

Placenta Growth Factor and Soluble Fms-Like Tyrosine Kinase 1 in Preeclampsia and Normotensive Pregnant Nigerian Women

Background: Preeclampsia (PE) is still one of the leading causes of maternal/perinatal morbidity/mortality in Nigeria. Imbalance between placenta growth factor (PLGF) and soluble fms-like tyrosine kinase 1 (sFlt1) has been reportedly present both before and after the manifestation of PE; however, Nigerian data regarding these angiogenesis-related substances are lacking. We here attempted to determine the maternal serum level of PLGF and sFlt1 and sFlt1/PLGF ratio in PE vs. non-PE women in Lagos State University Teaching Hospital, Nigeria. Methods: An observational cross-sectional study was made on 75 women with PE and 75 age-gestational-age matched women without PE, as case and control, respectively. Levels of sFlt-1, PIGF and the sFlt-1: PIGF ratio was compared between the two. Results: Serum levels of Flt-1 and sFlt1/PIGF ratio were significantly higher in PE patients (6581.86 ± 865.75, and 146.42 ± 92.43) than in the normotensive control (4584.52 ± 1479.6 and 11.60 ± 6.42). PIGF was significantly lower in PE patients (70.14 ± 51.03) than the normotensives (494.06 ± 475.8). There were positive and negative correlations between the sFlt-1 and PLGF respectively and mean arterial blood pressure. Conclusion: Serum sFlt-1, sFlt1/PIGF ratio was significantly higher and PIGF levels were significantly lower in PE than normotensive control in Nigerian population.

Angiogenic cytokines can reflect the synovitis severity and treatment response to biologics in rheumatoid arthritis

Angiogenesis and synoviocyte hyperplasia, called ‘pannus,’ are pathologic hallmarks of rheumatoid arthritis (RA). To determine the clinical significance of angiogenic cytokines in RA, the levels of pro-angiogenic cytokines, including VEGF, placenta growth factor (PlGF), and IL-6, were measured in the synovial fluid (SF, n = 54) and sera of RA patients (n = 157) using ELISA. Patients (n = 103) with disease activity score 28 (DAS28) > 3.2, which indicates moderate to high RA activity, underwent follow-up blood sampling at 6 months after treatment with conventional disease-modifying anti-rheumatic drugs (c-DMARD) or biologic DMARD (b-DMARD) including an anti-TNFα antibody, an anti-IL-6 antibody, and abatacept. Ultrasonography (US) was performed on affected joints to define the synovitis severity at the time of sampling. Consequently, in the SF of RA patients, PlGF and IL-6 levels correlated well with synovitis severity determined by US. In RA sera, VEGF and IL-6 levels were elevated in proportion to synovitis severity, correlating with conventional markers for disease activity, including ESR, CRP, and DAS28. In c-DMARD users (n = 53), serially monitored levels of serum VEGF, IL-6, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) all decreased in good and moderate responders but not in nonresponders. In b-DMARD users (n = 49), only serum VEGF well represented the treatment response, while CRP nonspecifically decreased irrespective of the treatment outcome. By multivariable analysis, serum ΔVEGF, but not ΔESR or ΔCRP, was an independent factor associated with good and moderate responses to DMARD. In summary, the angiogenic cytokines PlGF and VEGF represent the synovitis severity of RA assessed by US. In patients receiving b-DMARD, serum VEGF may be more valuable than CRP in reflecting the treatment response.

Conditioned medium derived from FGF-2-modified GMSCs enhances migration and angiogenesis of human umbilical vein endothelial cells

BackgroundAngiogenesis plays an important role in tissue repair and regeneration, and conditioned medium (CM) derived from mesenchymal stem cells (MSC-CM) possesses pro-angiogenesis. Nevertheless, the profile and concentration of growth factors in MSC-CM remain to be optimized. Fibroblast growth factor-2 (FGF-2) has been proven to be an effective angiogenic factor. Thus, the aim of this study was to verify whether FGF-2 gene overexpression optimized CM from human gingival mesenchymal stem cells (hGMSCs) and whether such optimized CM possessed more favorable pro-angiogenesis effect.MethodsFirst, FGF-2 gene-modified hGMSCs were constructed using lentiviral transfection technology (LV-FGF-2+-hGMSCs) and the concentration of angiogenesis-related factors in LV-FGF-2+-hGMSC-CM was determined by ELISA. Then, human umbilical vein endothelial cells (HUVECs) were co-cultured for 3 days with LV-FGF-2+-hGMSC-CM, and the expression level of placenta growth factor (PLGF), stem cell factor (SCF), vascular endothelial growth factor receptor 2 (VEGFR2) in HUVECs were determined by qRT-PCR, western blot, and cellular immunofluorescence techniques. The migration assay using transwell and in vitro tube formation experiments on matrigel matrix was conducted to determine the chemotaxis and angiogenesis enhanced by LV-FGF-2+-hGMSC-CM. Finally, NOD-SCID mice were injected with matrigel mixed LV-FGF-2+-hGMSC-CM, and the plug sections were analyzed by immunohistochemistry staining with anti-human CD31 antibody.ResultsLV-FGF-2+-hGMSC-CM contained significantly more FGF-2, vascular endothelial growth factor A (VEGF-A), and transforming growth factor β (TGF-β) than hGMSC-CM. HUVECs pretreated with LV-FGF-2+-hGMSC-CM expressed significantly more PLGF, SCF, and VEGFR2 at gene and protein level than hGMSC-CM pretreated HUVECs. Compared with hGMSC-CM, LV-FGF-2+-hGMSC-CM presented significantly stronger chemotaxis to HUVECs and significantly strengthened HUVECs mediated in vitro tube formation ability. In vivo, LV-FGF-2+-hGMSC-CM also possessed stronger promoting angiogenesis ability than hGMSC-CM.ConclusionsOverexpression of FGF-2 gene promotes hGMSCs paracrine of angiogenesis-related growth factors, thereby obtaining an optimized conditioned medium for angiogenesis promotion.

Comparison of aqueous humor levels of PlGF and VEGF in proliferative diabetic retinopathy before and after intravitreal conbercept injection

AimsThe aim of this paper is to observe the change of aqueous humor levels of placenta growth factor (PlGF) and vascular endothelial growth factor (VEGF) in proliferative diabetic retinopathy (PDR) patients before and one week after intravitreal conbercept injection. MethodsA prospective case series study was conducted in 24 active PDR patients (24 eyes). All the patients had received 0.5 mg of intravitreal conbercept followed by vitrectomy one week later. The aqueous humor was collected before conbercept injection and at the beginning of vitrectomy. ResultsBefore conbercept injection, the aqueous humor median levels of VEGF-A, VEGF-B and PlGF were457.0pg/mL(IQRfrom392.9to860.6pg/mL), 43.6pg/mL(IQRfrom33.6to81.6pg/mL), 37.5pg/mL(IQRfrom25.0to53.6pg/mL), respectively. One week after conbercept injection, the aqueous humor levels of VEGF-A, VEGF-B and PiGF decreased significantly. The aqueous humor VEGF-A levels in PDR patients with fibrovascular membranes were lower than those without them. There was positive correlation between aqueous humor VEGF-B and PiGF levels (P = 0.007). No significant correlation was found between VEGF-A and PiGF levels. No ocular and systemic adverse events were observed. ConclusionsThe aqueous humor levels of PlGF was correlated with VEGF-B, and levels of VEGF-A, VEGF-B, and PlGF decreased after intravitreal conbercept injection in active PDR patients.

Genetic interaction between placental growth factor and vascular endothelial growth factor A in psoriasis.

SummaryBackgroundExpression of vascular endothelial growth factor A (VEGFA) is increased in chronic inflammatory skin diseases, including psoriasis, and loci for two VEGFA single nucleotide polymorphisms are associated with early‐onset psoriasis (presenting before the age of 40 years). Studies have suggested that expression of placenta growth factor (PGF) is also upregulated in cutaneous inflammation and that VEGFA‐mediated angiogenesis may be dependent on the simultaneous presence of PGF within the skin.AimTo elucidate the biological importance of PGF in psoriasis.MethodsWe investigated whether two commonly occurring PGF polymorphisms were associated with early‐onset psoriasis and the genetic interaction between VEGFA and PGF in psoriasis.ResultsWe observed a significant (P = 0.04) association between rs2268614 TT and rs2268615 AA genotypes of PGF and early‐onset psoriasis. In addition, genetic complement, comprising the PGF rs2268615 AA genotype and the VEGFA −460 (rs833061) T allele, was significantly associated with the development of early‐onset psoriasis (P < 0.03). We identified that the VEGFA genotype influences PGF expression (P = 0.001) and that mean plasma levels of PGF are lower in patients with severe psoriasis compared with those with mild–moderate disease (P = 0.04).ConclusionOur observed genetic interaction between PGF and VEGFA appears relevant to psoriasis, a disease with an angiogenic basis, and may influence development of an antiangiogenic approach to treatment.

Free heme regulates placenta growth factor through NRF2-antioxidant response signaling

Free heme activates erythroblasts to express and secrete Placenta Growth Factor (PlGF), an angiogenic peptide of the VEGF family. High circulating levels of PlGF have been associated in experimental animals and in patients with sickle cell disease with echocardiographic markers of pulmonary hypertension, a life-limiting complication associated with more intense hemolysis. We now show that the mechanism of heme regulation of PlGF requires the contribution of the key antioxidant response regulator NRF2. Mimicking the effect of heme, the NRF2 agonist sulforaphane stimulates the PlGF transcript level nearly 30-fold in cultured human erythroblastoid cells. Heme and sulforaphane also induce transcripts for NRF2 itself, its partners MAFF and MAFG, and its competitor BACH1. Furthermore, heme induction of the PlGF transcript is significantly diminished by the NRF2 inhibitor brusatol and by siRNA knockdown of the NRF2 and/or MAFG transcription factors. Chromatin immunoprecipitation experiments show that heme induces NRF2 to bind directly to the PlGF promoter region. In complementary in vivo experiments, mice injected with heme show a significant increase in their plasma PlGF protein as early as 3 h after treatment. Our results reveal an important mechanism of PlGF regulation, adding to the growing literature that supports the pivotal importance of the NRF2 axis in the pathobiology of sickle cell disease.

Using serum placenta growth factor could improve the sensitivity of colorectal cancer screening in fecal occult blood negative population: A multicenter with independent cohort validation study.

BackgroundColorectal cancer (CRC) is one of the most common cancers worldwide. Screening for CRC using the fecal occult blood test (FOBT) is feasible and useful for decreasing disease‐related mortality; however, its sensitivity and compliance are unsatisfactory.MethodsThis study examined the efficacy of using serum placenta growth factor (PlGF) for a novel CRC screening strategy. To investigate a potential novel screening tool for CRC, we compared the sensitivity, specificity, positive predictive value, and negative predictive value of the FOBT, serum PlGF, and their combination through an examination of two independent cohorts and validation using the second cohort. All the patients and control group received the colonoscopy and FOBT, the colonoscopy was used as the gold standard for the result.ResultsSerum PlGF levels were significantly increased in CRC patients (16.8 ± 11.4 pg/mL) compared with controls (12.0 ± 11.2 pg/mL). The predictive model that used the serum PlGF level alone was as effective as the FOBT (AUC: 0.60 vs 0.68, P = 0.891), and it had significantly higher sensitivity than the FOBT (0.81 vs 0.39). In addition, we found serum PlGF level has a good value for predicting CRC patients in those FOBT negative populations. Finally, combining serum PlGF level and the FOBT improved the predictive power and demonstrated satisfactory sensitivity (0.71) and specificity (0.71). This result was confirmed and validated in the second independent cohort. Furthermore, no matter the stages (early/advanced) and the location (distal/proximal) of CRC, the efficacy of serum PlGF and the combined model remained quite stable.ConclusionSerum PlGF level is a potential alternative screening tool for CRC, especially for those who are reluctant to stool‐based screening methods and who were tested as negative FOBT. In addition, combining serum PlGF level and the FOBT could increase the power of CRC screening.