Levels Of Antiangiogenic Proteins Research Articles

Biochemical markers in the pathogenesis of preeclampsia: novel link between placental growth factor and interleukin-6.

Preeclampsia (PE) is a multisystem disorder of pregnancy characterized by sudden onset of hypertension and proteinuria. The appearance and diagnosis of the disease remain elusive and the only treatment is the termination of pregnancy. The onset of the disease is preceded by a shift in the balance of the angiogenic and antiangiogenic proteins in the maternal circulation. We surmised that the assessment of the levels of these proteins during pregnancy could lead to a proper diagnosis of the disease. In this study, we determined the levels of angiogenic and antiangiogenic proteins and IL-6 in maternal circulation during normotensive and hypertensive pregnancy, including PE. Serum isolated from pregnant women during antenatal visits was used to determine the concentrations of these proteins. The levels of antiangiogenic proteins, sFlt-1 and sEng, were higher in hypertensive disorders [gestational hypertension (GH), mild PE, and PE] of pregnancy and were significantly higher for PE than for GH. The levels of sFlt-1 and sEng were higher in PE samples compared to those in GH and NT samples. These proteins may have contributed to increased blood pressure. The levels of PlGF were decreased in pregnant women having GH, mild PE, and PE. The levels of the inflammatory intermediate, IL-6, were increased in PE samples compared to those in the GH and normotensive samples. The evaluation of the altered levels of antiangiogenic and angiogenic proteins can be useful for diagnosis of PE.

OP 41 Postpartum levels of maternal anti-angiogenic proteins in hypertensive disorders of pregnancy

Background Levels of anti-angiogenic proteins (soluble fms-like tyrosine kinase [sFlt1] and soluble endoglin [sEng]) are elevated during pregnancy in women with hypertensive disorders of pregnancy (HDP). The objective was to assess whether women with HDP have an angiogenic factor imbalance in the postpartum period that may predispose them to a future cardiovascular disease. Methods This is a secondary analysis of a prospective study of singleton pregnancies in which anti-angiogenic proteins and cardiovascular function was assessed throughout pregnancy and up to one year postpartum. sFlt1 (pg/ml) and sEng (ng/ml) were measured by ELISA. Women with preeclampsia, were labeled as proteinuric hypertension and gestational/chronic hypertension were labeled as non-proteinuric hypertension. Comparison of baseline characteristics and anti-angiogenic factors was assessed with a parametric or non-parametric t -test, as appropriate. Results Of 86 patients with both antepartum and postpartum levels of angiogenic factors, 25 were normal, 26 had non-proteinuric hypertension and 35 had proteinuric hypertension. Antepartum levels of anti-angiogenic proteins were significantly elevated in proteinuric hypertension (median sFlt1 15955.9, IQR: 8207.1–20076.4; sEng 32.0, IQR: 15.4–56.9) in comparison to non-proteinuric hypertension (sFlt1 5567.7, IQR: 3340.4–7077.9; sEng 13.5, IQR: 8.1–20.2) and normal patients (sFlt1 1915.76, IQR: 1263.65–4357.84; sEng 8.21, IQR: 5.44–11.46; all p p = 0.87) or sEng (means 4.69, 4.41, and 4.05 for normal, non-proteinuric and proteinuric hypertension, respectively; p = 0.20). There was no significant difference in postpartum levels at 3, 6 or 12 months. Conclusion Postpartum circulating plasma levels of anti-angiogenic factors were not different among women who were hypertensive during pregnancy compared to normal women. Interactions of angiogenic proteins with other factors or local abnormality in angiogenesis in specific organs such as the heart may be contributing to increased long-term cardiovascular morbidity among these women.

5 Myocardial performance index and anti angiogenic factors among women with preeclampsia

Introduction Soluble anti angiogenic proteins have been known to be elevated in women with preeclampsia and have been associated with worsening systolic and diastolic function. Myocardial performance index (MPI) also known as the TEI Index is a tissue Doppler derived measure of global cardiac function that is used to assess both systolic and diastolic function. MPI is defined as the sum of the Isovolumic contraction time and the Isovolumic relaxation time divided by the ejection time. Smaller MPI values signify shorter relative Isovolumic contraction or relaxation times and thus indicate better overall function. Physiologically, left ventricular systolic function is better when a greater fraction of systolic time is spent ejecting rather than in isovolumic contraction. Similarly, better diastolic function is represented by a greater portion of diastole spent filling rather than in isovolumic relaxation. Previous work has demonstrated that cardiac time intervals are sensitive markers of subclinical cardiac dysfunction despite there being no changes detected by conventional echocardiography. In contrast to ejection fraction, MPI is independent of ventricular geometry, preload and heart rate. Objective The purpose of this study was to study myocardial performance index among women with preeclampsia and correlate MPI with circulating anti angiogenic factor levels. Methods One hundred twenty one women with diagnosis of preeclampsia ( n = 48), normal pregnancy ( n = 73) were studied. Plasma was collected and levels of anti angiogenic proteins (soluble fms like tyrosine kinase- sFlt1 and soluble endoglin sEng) were measured using enzyme linked immune sorbent assay. All patients had an echocardiogram performed at the time of diagnosis. Blood sample were collected within 24 hours of echocardiogram. Results Patients with preeclampsia had higher mean sFlt1 (pg/ml) and sEng (ng/ml) compared to normal patients (19243 vs 3816 and 47 vs 11, respectively, both p p = 0.04). Worsening MPI was significantly correlated to increasing sFlt1 ( p = 0.04) and sEng levels ( p = 0.03). In addition we found worsening left ventricular relaxation times to be correlated with increasing sFlt1 and sEng levels (both p Discussion/conclusion Worsening myocardial performance as measured by MPI was seen among women with preeclampsia and these changes correlated with increasing antiangiogenic factors like sFlt1 and sEng. Further studies are needed to validate these findings and evaluate whether these changes remain persistent postpartum.

27 Circulating antiangiogenic factors and myocardial dysfunction in hypertensive disorders of pregnancy

Introduction Hypertensive disorders of pregnancy (HDP) are associated with subclinical changes in cardiac function. Although the mechanism underlying this finding is unknown, elevated levels of soluble antiangiogenic proteins such as soluble fmslike tyrosine kinase-1 (sFlt1) and soluble endoglin (sEng) are associated with myocardial dysfunction and may play a role. We hypothesized that these antiangiogenic proteins may contribute to the development of cardiac dysfunction in HDP. Methods We prospectively studied 207 pregnant women with HDP and nonhypertensive controls and evaluated whether changes in global longitudinal strain (GLS) observed on echocardiography is specific for HDP and whether these changes correlate with HDP biomarkers, sFlt1 and sEng. A total of 62 (30%) patients were diagnosed with preeclampsia (group A), 105 (51%) did not have an HDP (group B), and 40 (19%) were diagnosed with chronic or gestational hypertension (group C). Blood was drawn and sFlt1 and sEng levels measured using enzyme-linked immunosorbent assay. Comprehensive echocardiograms, including measurement of GLS, were performed on all patients. Results Overall, GLS was worse in women in group A (preeclampsia) than those in group B or C. Increasing sFlt1 and sEng levels correlated with worsening GLS ( r = 0.44 for sFlt1 and r = 0.46 for sEng, both P r = 0.18 and r = 0.22, both P ⩽ 0.01). Increasing levels also correlated with increasing left ventricular mass index, which also remained significant after multivariable analysis ( r = 0.20 for sFlt1 and 0.19 for sEng, both P = 0.01). Conclusion Elevated circulating levels of antiangiogenic proteins in HDP correlate with and may contribute to myocardial dysfunction as measured by GLS.

Anti-angiogenic effects of liposomal prednisolone phosphate on B16 melanoma in mice

Prednisolone phosphate (PLP) encapsulated in long-circulating liposomes can inhibit tumor growth after intravenous administration (i.v.). These antitumor effects of liposomal PLP are the result of the tumor-targeting property of the liposome formulation. The mechanism by which liposomal PLP inhibits tumor growth is unclear. We investigated the effects of liposome-encapsulated PLP versus free PLP on angiogenic protein production in tumor tissue in vivo and on viability and proliferation of tumor and endothelial cells in vitro. In vivo, liposomal PLP had a stronger reducing effect on pro-angiogenic protein levels than free PLP, whereas levels of anti-angiogenic proteins were hardly affected. Cell viability was only slightly affected with either treatment. Liposomal PLP had strong anti-proliferative effects on human umbilical vein endothelial cells, whereas free PLP had hardly any effect. Taken together, the present study points to a strong inhibitory effect of liposomal PLP on tumor angiogenesis by reduction of the intratumoral production of the majority of pro-angiogenic factors studied and direct inhibition of endothelial cell proliferation, which is the result of high prolonged levels of prednisolone in the tumor by liposomal delivery.