Soluble Endoglin Stimulates Inflammatory and Angiogenic Responses in Microglia That Are Associated with Endothelial Dysfunction

Increased soluble endoglin (sENG) were observed in human brain arteriovenous malformations (bAVMs), and overexpression of sENG with vascular endothelial growth factor (VEGF)-A induced dysplastic vessel formation in mouse brain. However, the underlying mechanism of sENG-induced vascular malformations is not clear. While evidence suggests the role of sENG as a pro-inflammatory modulator, increased microglial accumulation and inflammations were observed in bAVMs. Therefore, we hypothesized that microglia mediate sENG-induced inflammation and endothelial cell (EC) dysfunction in bAVMs. In this study, we confirmed that sENG with VEGF-A overexpression induced dysplastic vessel formation. Remarkably, there were increased microglial activation around dysplastic vessels with expression of NLRP3, inflammasome marker. We found that sENG increased the gene expression of VEGF-A, pro-inflammatory cytokines/inflammasome mediators (TNF-α, IL-6, NLRP3, ASC, Caspase-1, and IL-1β), and proteolytic enzyme (MMP-9) in BV2 microglia. The conditioned media from sENG-treated BV2 (BV2-sENG-CM) significantly increased angiogenic factors (Notch-1 and TGFβ) and pERK1/2 in ECs while it decreased IL-17RD, an anti-angiogenic mediator. Finally, the BV2-sENG-CM significantly increased EC migration and tube formation. Together, our study demonstrates that sENG provokes microglia to release angiogenic/inflammatory responses which may be involved in EC dysfunction. Our study suggests the contribution of microglia in the pathology of sENG-associated vascular malformations.

High Soluble Endoglin Levels Affect Aortic Vascular Function during Mice Aging

Endoglin is a 180 kDa transmembrane glycoprotein that was demonstrated to be present in two different endoglin forms, namely membrane endoglin (Eng) and soluble endoglin (sEng). Increased sEng levels in the circulation have been detected in atherosclerosis, arterial hypertension, and type II diabetes mellitus. Moreover, sEng was shown to aggravate endothelial dysfunction when combined with a high-fat diet, suggesting it might be a risk factor for the development of endothelial dysfunction in combination with other risk factors. Therefore, this study hypothesized that high sEng levels exposure for 12 months combined with aging (an essential risk factor of atherosclerosis development) would aggravate vascular function in mouse aorta. Male transgenic mice with high levels of human sEng in plasma (Sol-Eng+) and their age-matched male transgenic littermates that do not develop high soluble endoglin (Control) on a chow diet were used. The aging process was initiated to contribute to endothelial dysfunction/atherosclerosis development, and it lasted 12 months. Wire myograph analysis showed impairment contractility in the Sol-Eng+ group when compared to the control group after KCl and PGF2α administration. Endothelium-dependent responsiveness to Ach was not significantly different between these groups. Western blot analysis revealed significantly decreased protein expression of Eng, p-eNOS, and ID1 expression in the Sol-Eng+ group compared to the control group suggesting reduced Eng signaling. In conclusion, we demonstrated for the first time that long-term exposure to high levels of sEng during aging results in alteration of vasoconstriction properties of the aorta, reduced eNOS phosphorylation, decreased Eng expression, and altered Eng signaling. These findings suggest that sEng can be considered a risk factor for the development of vascular dysfunction during aging and a potential therapeutical target for pharmacological intervention.

Soluble Endoglin and Uterine Artery Flow Doppler Ultrasonography as Markers of Progression to Preeclampsia in Women with Gestational Hypertension

<b><i>Introduction:</i></b> Gestational hypertension (GH) pregnancies are at a high risk of developing adverse outcomes, including progression to preeclampsia. Prediction of GH-related adverse outcomes is challenging because there are no available clinical tests that may predict their occurrence. <b><i>Objective:</i></b> The aim of the study was to determine the clinical usefulness of the soluble endoglin (sEng) and parameters of uterine artery flow (UtAF) measured by Doppler ultrasonography as markers of progression to preeclampsia in women with GH. <b><i>Setting:</i></b> Mexico City, Mexico. <b><i>Material and Methods:</i></b> We included 77 singleton pregnant women with GH in a nested case-control study. Cases were women who progressed to preeclampsia (<i>n</i> = 36), and controls were those who did not <b>(</b><i>n</i> = 41). Serum sEng and UtAF measurements were performed at enrollment. The main outcomes measured were progression to preeclampsia and occurrence of preterm delivery (PD) &#x3c;37 and &#x3c;34 weeks of gestation, small for gestational age infant (SGA), and fetal growth restriction (FGR). <b><i>Results:</i></b> Women with sEng values in the highest tertile had higher risk of progression to preeclampsia, preterm delivery &#x3c;34 weeks of gestation, and fetal growth restriction, odds ratios (ORs) ≥3.7. Patients with abnormal UtAF Dopp­ler-pulsatility index had higher risk of progression to preeclampsia, preterm delivery &#x3c;34 weeks of gestation, small for gestational age infant, and fetal growth restriction (ORs ≥3.3). The presence of notch was associated with higher risk of progression to preeclampsia, preterm delivery &#x3c;37 and &#x3c;34 weeks of gestation, SGA infant, and fetal growth restriction (ORs ≥2.9). However, logistic regression analysis revealed that only serum sEng was a significant and independent risk factor for progression of GH to preeclampsia, preterm delivery &#x3c;34 weeks of gestation, and fetal growth restriction (ORs ≥3.1). <b><i>Conclusions:</i></b> In GH pregnancies, UtAF Doppler ultrasonography is associated with increased risk of adverse outcomes and progression to preeclampsia. However, serum sEng concentration appears to be a better predictor to assess the risk of adverse maternal and perinatal outcomes and progression to preeclampsia.

Relationship of soluble Fms-like tyrosine kinase 1, soluble endoglin, placental growth factor blood levels with the severity of late onset preeclampsia

Purpose: Preeclampsia (PE) is a pregnancy-specific syndrome characterized by placentation disorder that increases maternal and fetal morbidity and mortality. Overproduction of anti-angiogenic factors such as soluble fms-like tyrosine kinase receptor 1 (sFlt-1) and soluble endoglin (sEng) and low production of placental growth factor (Pgf) from angiogenic factors contribute to preeclampsia pathogenesis. In this study, factors involved in angiogenesis including sEng, Pgf and sFlt1 were investigated for pre-recognition of preeclampsia. Methods: A total of 54 pregnant women were included in the study and the patients were divided into normotensive (n = 25) and preeclampsia groups (n = 29). Both groups demographic characteristics, laboratory parameters, sEng, sFlt1 and placental growth factor levels were compared. Results: While AST, uric acid, LDH mean values were significantly higher in the study group compared to the control group (p<0.05), there was no significant difference between the groups in terms of ALT, creatinin, hemoglobin, leucocyte, and platelet values. sEng, sFlt1 values were significantly lover in the preeclampsia group compared to the control group (p<0.05). Conclusion: it is thought that Pgf may have a place in the prediction of preeclampsia in advanced pregnancy weeks, but sFlt-1 and sEng are weak in predicting preeclampsia in advanced pregnancy weeks as well.

Maternal Immune System and State of Inflammation Dictate the Fate and Severity of Disease in Preeclampsia

Preeclampsia, a multisystem disorder in pregnant women, is diagnosed by onset of new hypertension, proteinuria, or organ damage. Antiangiogenic factors, such as soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng), are long known to be involved in preeclampsia. However, the role of maternal immune system and inflammation in promotion of preeclampsia has lately been a subject of immense interest. Link between maternal inflammation and preeclampsia is not well established. Furthermore, whether cigarette smoke promotes inflammation and also promotes severity of preeclampsia remains an open question. We herein investigated correlation of established inflammation signatures in the plasma and placental tissue from cohorts of preterm preeclampsia (PPE) and preterm pregnancies (control) with or without smoking history. Besides confirming increased levels of Flt1 and Eng in preeclampsia, we also observed an increase in various mediators of maternal inflammation in women with PPE compared to preterm cohort. Increased IL-6, IL-35, and TNF-α and reduced IL-10 in serum and higher MMP-12, TLR4, HMGB-1, and iNOS and lower Foxp3, CD56 transcripts in placental tissues of PPE compared to preterm pregnancies indicate an association of preterm preeclampsia with stark imbalance in maternal immune system and signatures of inflammation. Smoker PPE cohorts showed highest inflammatory signatures including statistically significant increase for many signatures compared to other cohorts. Together, these results provide evidence for association of inflammation with PPE and strong correlation of smoking with inflammatory signatures in PPE.