ANGIOGENIC IMBALANCES IN THE PATHOGENESIS OF PREGNANCY COMPLICATIONS

2014 ◽  
Vol 25 (1) ◽  
pp. 42-58
Author(s):  
JIMMY ESPINOZA
Keyword(s):  
Pregnancy Complications ◽  
Angiogenic Factors ◽  
Angiogenic Factor ◽  
Soluble Form ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Maternal Circulation ◽  
Soluble Endoglin ◽  
Endothelial Growth Factor

Endothelial cell proliferation and survival require continuous low levels of vascular endothelial growth factor (VEGF). The bioavailability of this angiogenic factor appears to be regulated by anti-angiogenic factors, including the soluble form of VEGF receptor 1 (sFlt-1) in the non-pregnant and pregnant states. During pregnancy a VEGF antagonist (sFlt-1) and other anti-angiogenic factors, including soluble endoglin (s-Eng), are produced by the human placenta and released into the maternal circulation; an excess of these anti-angiogenic factors can lead into angiogenic imbalances and pregnancy complications. This is important because regulation of VEGF action on angiogenic balances appears to be essential for a successful pregnancy.

scholarly journals VEGF-A-Cleavage by FSAP and Inhibition of Neo-Vascularization

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1396 ◽  
Author(s):  
Özgür Uslu ◽  
Joerg Herold ◽  
Sandip M. Kanse
Keyword(s):  
Growth Factor ◽  
Tissue Injury ◽  
Factor Vii ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
The Matrix ◽  
Endothelial Growth Factor

Alternative splicing leads to the secretion of multiple forms of vascular endothelial growth factor-A (VEGF-A) that differ in their activity profiles with respect to neovascularization. FSAP (factor VII activating protease) is the zymogen form of a plasma protease that is activated (FSAPa) upon tissue injury via the release of histones. The purpose of the study was to determine if FSAPa regulates VEGF-A activity in vitro and in vivo. FSAP bound to VEGF165, but not VEGF121, and VEGF165 was cleaved in its neuropilin/proteoglycan binding domain. VEGF165 cleavage did not alter its binding to VEGF receptors but diminished its binding to neuropilin. The stimulatory effects of VEGF165 on endothelial cell proliferation, migration, and signal transduction were not altered by FSAP. Similarly, proliferation of VEGF receptor-expressing BAF3 cells, in response to VEGF165, was not modulated by FSAP. In the mouse matrigel model of angiogenesis, FSAP decreased the ability of VEGF165, basic fibroblast growth factor (bFGF), and their combination, to induce neovascularization. Lack of endogenous FSAP in mice did not influence neovascularization. Thus, FSAP inhibited VEGF165-mediated angiogenesis in the matrigel model in vivo, where VEGF’s interaction with the matrix and its diffusion are important.

Abstract 129: A Biopolymer-Stabilized VEGF Chimera Reverses Angiogenic Imbalance in vitro in the Reduced Uterine Perfusion Pressure Model of Preeclampsia

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Omar C Logue ◽  
Fakhri Mahdi ◽  
Eric M George ◽  
Gene L Bidwell
Keyword(s):  
Perfusion Pressure ◽  
Placental Transfer ◽  
Umbilical Vein ◽  
Angiogenic Factors ◽  
Angiogenic Factor ◽  
Unknown Etiology ◽  
Vegf Receptor ◽  
Hypertensive Disorder ◽  
Vascular Endothelial ◽  
Uterine Perfusion

Preeclampsia (PE) is a hypertensive disorder that complicates approximately 5-8% of all pregnancies in the U.S. The unknown etiology of PE develops from molecular dysfunction at the maternal-placental interface, where inflammatory, oxidative stress, and anti-angiogenic pathways are initiated. The resulting hypoxic in utero environment contributes to placental ischemia from which the anti-angiogenic factor soluble fms-like tyrosine kinase-1 (sFlt-1) is released. A truncated isoform, sFlt-1 consists solely of the extracellular domain of the vascular endothelial growth factor (VEGF) receptor 1, and hence lacks both catalytic and regulatory activities. However, sFlt-1 retains a high affinity for VEGF and sequesters this ligand from binding with fully functional VEGF receptors, thus prevents the activation of angiogenic remodeling pathways. The rodent model of PE, reduced uterine perfusion pressure (RUPP), exhibits the sFlt-1 pathophysiology observed in human PE. In an effort to counteract excessive sFlt-1 production and restore angiogenic balance, we have constructed a VEGF chimera fused to an Elastin-like Polypeptide (ELP) carrier with increased in vivo half-life and stability which retains full VEGF signaling activity. When human umbilical vein vascular endothelial cells (HUVECs) are exposed to serum from normal pregnant or RUPP-treated rats, tube formation on extracellular matrix is inhibited 31% (± 2%) by the RUPP serum. This inhibition is reversed when ELP-VEGF, but not ELP control, is added to the culture medium ( p = 0.0007, one-way ANOVA with Bonferroni multiple comparison), suggesting that ELP-VEGF counteracts the anti-angiogenic factors present in RUPP serum. We also characterized the pharmacokinetics, biodistribution, and placental transfer of ELP-VEGF in the pregnant Sprague Dawley rat. These studies indicate that ELP-delivered VEGF has potential for counteracting the circulating anti-angiogenic factors in maternal plasma.

scholarly journals Angiogenic factor signaling regulates centrosome duplication in endothelial cells of developing blood vessels

Blood ◽  
2010 ◽  
Vol 116 (16) ◽  
pp. 3108-3117 ◽  
Author(s):  
Sarah M. Taylor ◽  
Kathleen R. Nevis ◽  
Hannah L. Park ◽  
Gregory C. Rogers ◽  
Stephen L. Rogers ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Angiogenic Factors ◽  
Angiogenic Factor ◽  
Centrosome Duplication ◽  
Vascular Endothelial ◽  
Vegf Signaling ◽  
Vessel Networks ◽  
Endothelial Growth Factor ◽  
Cellular Dysfunction

Abstract Regulated vascular endothelial growth factor (VEGF) signaling is required for proper angiogenesis, and excess VEGF signaling results in aberrantly formed vessels that do not function properly. Tumor endothelial cells have excess centrosomes and are aneuploid, properties that probably contribute to the morphologic and functional abnormalities of tumor vessels. We hypothesized that endothelial cell centrosome number is regulated by signaling via angiogenic factors, such as VEGF. We found that endothelial cells in developing vessels exposed to elevated VEGF signaling display centrosome overduplication. Signaling from VEGF, through either MEK/ERK or AKT to cyclin E/Cdk2, is amplified in association with centrosome overduplication, and blockade of relevant pathway components rescued the centrosome overduplication defect. Endothelial cells exposed to elevated FGF also had excess centrosomes, suggesting that multiple angiogenic factors regulate centrosome number. Endothelial cells with excess centrosomes survived and formed aberrant spindles at mitosis. Developing vessels exposed to elevated VEGF signaling also exhibited increased aneuploidy of endothelial cells, which is associated with cellular dysfunction. These results provide the first link between VEGF signaling and regulation of the centrosome duplication cycle, and suggest that endothelial cell centrosome overduplication contributes to aberrant angiogenesis in developing vessel networks exposed to excess angiogenic factors.

scholarly journals VEGF is a chemoattractant for FGF-2–stimulated neural progenitors

2003 ◽  
Vol 163 (6) ◽  
pp. 1375-1384 ◽  
Author(s):  
Huanxiang Zhang ◽  
Laszlo Vutskits ◽  
Michael S. Pepper ◽  
Jozsef Z. Kiss
Keyword(s):  
Nervous System ◽  
Growth Factor ◽  
Neural Progenitors ◽  
Angiogenic Factor ◽  
Fibroblast Growth Factor 2 ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Guidance Cue ◽  
Endothelial Growth Factor ◽  
Chemotactic Effect

Mmigration of undifferentiated neural progenitors is critical for the development and repair of the nervous system. However, the mechanisms and factors that regulate migration are not well understood. Here, we show that vascular endothelial growth factor (VEGF)-A, a major angiogenic factor, guides the directed migration of neural progenitors that do not display antigenic markers for neuron- or glia-restricted precursor cells. We demonstrate that progenitor cells express both VEGF receptor (VEGFR) 1 and VEGFR2, but signaling through VEGFR2 specifically mediates the chemotactic effect of VEGF. The expression of VEGFRs and the chemotaxis of progenitors in response to VEGF require the presence of fibroblast growth factor 2. These results demonstrate that VEGF is an attractive guidance cue for the migration of undifferentiated neural progenitors and offer a mechanistic link between neurogenesis and angiogenesis in the nervous system.

scholarly journals Preeclampsia – Prediction and Monitoring Factors

2019 ◽  
Vol 20 (4) ◽  
pp. 287-294
Author(s):  
Jovan Rudic ◽  
Sasa Raicevic ◽  
Goran Babic
Keyword(s):  
Growth Factor ◽  
Fetal Outcome ◽  
Angiogenic Factors ◽  
Soluble Form ◽  
Vascular Endothelial ◽  
Predictive Algorithms ◽  
Effective Combination ◽  
Initiation Of Therapy ◽  
Endothelial Growth Factor

Abstract Preeclampsia is one of the leading causes of maternal and perinatal morbidity and mortality, usually characterized by hypertension and proteinuria. Despite high incidence of preeclampsia the pathophysiological basis of preeclampsia is still not clear and there are a number of mechanisms and signaling pathways that intertwine. It is very important to develop specific and reliable predictive algorithms in order to enable early initiation of therapy due to facts that incidence of preeclampsia has upward trend and that cause adverse maternal and fetal outcome. Some of the most commonly used methods for prediction of preeclampsia include uterine artery Doppler velocimetry, determination of some microRNA, such as miR-210, and assessment of various pro-angiogenic and anti-angiogenic factors from blood. Angiogenic factors that possibly have most important role in pathogenesis of preeclampsia are vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), which promote angiogenesis, and soluble fms-like tyrosine kinase-1 (sFlt1) and soluble form of endoglin (s-Eng), which exhibit anti-angiogenic properties. Aggravating circumstance is that preeclampsia has heterogeneous origin, and due to this fact, the value of individual markers can vary significantly. There is a constant tendency for creating comprehensive algorithm for prediction of preeclampsia which would be sufficiently specific and sensitive, and in the same time cheap and available. In that sense, new clinical studies are needed to show the most effective combination of parameters in the predeclampsia prediction.

Vascular endothelial growth factor accelerates compensatory lung growth after unilateral pneumonectomy

2007 ◽  
Vol 292 (3) ◽  
pp. L742-L747 ◽  
Author(s):  
Maromi K. Sakurai ◽  
Sang Lee ◽  
Danielle A. Arsenault ◽  
Vania Nose ◽  
Jay M. Wilson ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Growth Factor ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Lung Growth ◽  
Compensatory Lung Growth ◽  
Chemical Inhibitors ◽  
Proliferation And Apoptosis ◽  
Endothelial Growth Factor

We hypothesize that compensatory lung growth after unilateral pneumonectomy in a murine model is, in part, angiogenesis dependent and can be altered using angiogenic agents, possibly through regulation of endothelial cell proliferation and apoptosis. Left pneumonectomy was performed in mice. Mice were then treated with proangiogenic factors [vascular endothelial growth factor (VEGF); basic fibroblast growth factor (bFGF)], VEGF receptor antibodies (MF-1, DC101), and VEGF receptor small molecule chemical inhibitors. Lung volume and mass were measured. The lungs were analyzed using immunohistochemistry by CD31 staining, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling, type II pneumocytes staining, and proliferating cell nuclear antigen. Compensatory lung growth was complete by postoperative day 10 and was associated with diffuse apoptosis of endothelial cells and pneumocytes. This process was accelerated by VEGF, such that growth was complete by postoperative day 4 with similar associated apoptosis. bFGF had no effect on lung growth. MF-1 and DC101 had no effect. The VEGF receptor small molecule chemical inhibitors also had no effect. VEGF, but not bFGF, accelerates growth. VEGF receptor inhibitors do not block growth, suggesting that other proangiogenic factors play a role or can compensate for VEGF receptor blockade. Diffuse apoptosis, endothelial cell and pneumocyte, occurs at cessation of both normal compensatory and VEGF-accelerated growth. Angiogenesis modulators may control growth via regulation of endothelial cell proliferation and apoptosis, although the exact relationship between endothelial cells and pneumocytes has yet to be determined. The fact that bFGF did not accelerate growth in our model when it did accelerate regeneration in the liver model suggests that angiogenesis during organ regeneration is regulated in an organ-specific manner.

scholarly journals Spreds Are Essential for Embryonic Lymphangiogenesis by Regulating Vascular Endothelial Growth Factor Receptor 3 Signaling

2007 ◽  
Vol 27 (12) ◽  
pp. 4541-4550 ◽  
Author(s):  
Koji Taniguchi ◽  
Ri-ichiro Kohno ◽  
Toranoshin Ayada ◽  
Reiko Kato ◽  
Kenji Ichiyama ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Blood Vessels ◽  
Lymphatic Vessels ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Erk Activation ◽  
Factor C ◽  
Endothelial Growth Factor

ABSTRACT Spred/Sprouty family proteins negatively regulate growth factor-induced ERK activation. Although the individual physiological roles of Spred-1 and Spred-2 have been investigated using gene-disrupted mice, the overlapping functions of Spred-1 and Spred-2 have not been clarified. Here, we demonstrate that the deletion of both Spred-1 and Spred-2 resulted in embryonic lethality at embryonic days 12.5 to 15.5 with marked subcutaneous hemorrhage, edema, and dilated lymphatic vessels filled with erythrocytes. This phenotype resembled that of Syk −/− and SLP-76 −/− mice with defects in the separation of lymphatic vessels from blood vessels. The number of LYVE-1-positive lymphatic vessels and lymphatic endothelial cells increased markedly in Spred-1/2-deficient embryos compared with WT embryos, while the number of blood vessels was not different. Ex vivo colony assay revealed that Spred-1/2 suppressed lymphatic endothelial cell proliferation and/or differentiation. In cultured cells, the overexpression of Spred-1 or Spred-2 strongly suppressed vascular endothelial growth factor-C (VEGF-C)/VEGF receptor (VEGFR)-3-mediated ERK activation, while Spred-1/2-deficient cells were extremely sensitive to VEGFR-3 signaling. These data suggest that Spreds play an important role in lymphatic vessel development by negatively regulating VEGF-C/VEGFR-3 signaling.

scholarly journals Role of vascular endothelial growth factor on erythropoietin-related endothelial cell proliferation.

1998 ◽  
Vol 9 (11) ◽  
pp. 1998-2004
Author(s):  
M V Alvarez Arroyo ◽  
M A Castilla ◽  
F R González Pacheco ◽  
D Tan ◽  
A Riesco ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Mrna Expression ◽  
Angiogenic Factor ◽  
Structural Basis ◽  
Endothelial Cell Proliferation ◽  
Positive Interactions ◽  
Vascular Endothelial ◽  
Positive Interaction ◽  
Endothelial Growth Factor

The vascular actions of recombinant human erythropoietin (rhEPO) are of particular relevance for fully understanding rhEPO effects. This study examines the mechanisms of action of rhEPO on endothelial cells from bovine aorta (BAEC). First, the studies demonstrated that rhEPO acts on BAEC proliferation as a comitogenic growth factor in the presence of fetal calf serum (FCS). The main experimental findings disclosed that an interaction between rhEPO and vascular endothelial growth factor (VEGF) is instrumental for the growth-promoting action of rhEPO, as shown by the blockade (92.8+/-2.2% inhibition, P < 0.01) of the rhEPO-induced BAEC proliferation by a specific anti-VEGF antibody and by the capability of VEGF for substituting FCS in the induction of rhEPO-related BAEC proliferation (increase in BAEC number in the absence of FCS: 20 U/ml rhEPO alone, 0.3+/-2.8%; 5 x 10(-11) M VEGF alone, 52.9+/-3.1%; 20 U/ml rhEPO + 5 X 10(-11) M VEGF, 117.8+/-6.9%, P < 0.01 between the two agents combined with respect to each agent alone). The existence of a positive interaction between rhEPO and VEGF was further demonstrated by observing an increased cytosolic Ca2+ ([Ca2+]i) mobilization response to VEGF (10(-11)M) in BAEC pretreated or not with 20 U/ml rhEPO (delta[Ca2+]i = 704+/-111 versus 246+/-36 nM, respectively, P < 0.01). To further examine the mechanism of the potentiation of VEGF effect by rhEPO, we analyzed the mRNA expression of the VEGF receptors KDR/flk-1 and flt-1. The results disclosed that BAEC pretreatment with rhEPO upregulated the expression of both KDR/flk-1 and flt-1, therefore providing a structural basis for the aforementioned positive interactions between VEGF and rhEPO. Furthermore, inhibition by genistein suggests that tyrosine phosphorylation was involved in the VEGF receptor upregulation. The mechanisms identified in the present study disclose an interaction at the level of mRNA expression and functional effects between a hormone with predominantly hemopoietic effects, namely, erythropoietin, and an angiogenic factor, namely, VEGF. This relationship between rhEPO and VEGF might be of particular importance in neovascularization processes and in patients receiving rhEPO as a treatment.

scholarly journals Role of Vascular Endothelial Growth Factor in Maintenance of Pregnancy in Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (2) ◽  
pp. 900-910 ◽  
Author(s):  
Yoshiko Wada ◽  
Hiromi Ozaki ◽  
Naomichi Abe ◽  
Asami Mori ◽  
Kenji Sakamoto ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Critical Role ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Maternal Circulation ◽  
Sequence Of Events ◽  
High Level ◽  
Rats And Mice ◽  
Endothelial Growth Factor

It is well known that withdrawal of progesterone from the maternal circulation is a critical stimulus to parturition in rodents, such as rats and mice. However, mechanisms that determine the timing of progesterone withdrawal are not completely understood. In the present study, we examined whether the vascular endothelial growth factor (VEGF) system in the corpus luteum (CL) contributes to the regulation of circulating progesterone levels and acts as a determinant of the timing of parturition in mice. We found that reduction in the expression levels of VEGF and VEGF receptor-2 in the CL precedes the impairment of luteal circulation and a series of events leading to parturition (i.e., reduction of plasma progesterone, enhancement of myometrium contractility, and onset of parturition). Blocking of VEGF signaling by using the inhibitor of VEGFR tyrosine kinase KRN633 at mid-pregnancy caused a similar sequence of events and induced preterm birth. These results suggest that the VEGF system in the CL plays a critical role in maintaining a high level of circulating progesterone, and determining the timing of parturition in mice.

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