Use of dopamine agonists to target angiogenesis in women with endometriosis

2020 ◽  
Author(s):  
Nuria Pellicer ◽  
Daniela Galliano ◽  
Sonia Herraiz ◽  
Yu Z Bagger ◽  
Joan-Carles Arce ◽  
...  
Keyword(s):  
Medical Management ◽  
Dopamine Agonists ◽  
Cellular Proliferation ◽  
Ovarian Function ◽  
Lesion Size ◽  
Experimental Models ◽  
Plasminogen Activator Inhibitor 1 ◽  
Fiber Density ◽  
Endometrial Cells ◽  
Pai 1

Abstract Endometriosis requires medical management during a woman’s reproductive years. Most treatments aim to create a hypoestrogenic milieu, but for patients wishing to conceive, drugs that allow normal ovarian function are needed. Targeting angiogenesis, a hallmark of the disease, using dopamine agonists (DAs) is a promising strategy for endometriosis treatment. Herein, we review experimental and clinical data that investigate this concept. In experimental models of endometriosis, DAs (bromocriptine, cabergoline, quinagolide) downregulate proangiogenic and upregulate antiangiogenic pathways in inflammatory, endothelial and endometrial cells, blocking cellular proliferation and reducing lesion size. Impaired secretion of vascular endothelial growth factor (VEGF) and inactivation of its receptor type-2 are key events. VEGF inhibition also reduces nerve fiber density in lesions. In humans, quinagolide shows similar effects on lesions, and DAs reduce pain and endometrioma size. Moreover, a 20-fold downregulation of Serpin-1, the gene that encodes for plasminogen activator inhibitor 1 (PAI-1), has been observed after DAs treatment. Pentoxifylline, a PAI-1, increases pregnancy rates in women with endometriosis. Thus, the data support the use of DAs in the medical management of endometriosis to reduce lesion size and pain while maintaining ovulation. A combined approach of DAs and pentoxifylline is perhaps a smart way of targeting the disease from a completely different angle than current medical treatments.

scholarly journals Plasminogen activator inhibitor-1: The double-edged sword in apoptosis

2008 ◽  
Vol 100 (12) ◽  
pp. 1029-1036 ◽  
Author(s):  
Rashna D. Balsara ◽  
Victoria A. Ploplis
Keyword(s):  
Plasminogen Activator ◽  
Cellular Proliferation ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Protective Effects ◽  
Plasminogen Activator Inhibitor 1 ◽  
Functional Protein ◽  
Apoptotic Pathway ◽  
Activator Inhibitor ◽  
Pai 1

SummaryPlasminogen activator inhibitor type-1 (PAI-1) is a multi-functional protein. It is a fast-acting inhibitor of plasminogen activators; urokinase-plasminogen activator and tissue type plasminogen activator, and also plays an important role in regulating cell proliferation, adhesion, migration, and signal transduction pathways.These biological events are important processes during angiogenesis and restenosis. PAI-1 has been shown to regulate proliferation, migration, and apoptosis of vascular smooth muscle cells and endothelial cells.The ability of PAI-1 to regulate cellular proliferation and migration has been attributed to its ability to control plasmin production, modify signaling pathways, and its inherent multifactorial ability to bind to vitronectin and lipoprotein receptor-related protein.However,the mechanism by which PAI-1 regulates the apoptotic pathway is not well understood. Evidence from the literature suggests that PAI-1 or its deficiency alters key signalling pathways, such as the PI3-k/Akt and the Jak/STAT pathways, and is involved in maintaining endothelial cell integrity thereby regulating cell death. Other investigators have demonstrated that PAI-1 directly binds to caspases as a mechanism of PAI-1-mediated cellular apoptosis. Moreover, results from studies assessing the role of PAI-1 in apoptosis have suggested that PAI-1 can exert pathogenic or protective effects, which may be related to the disease model or type of injury employed.

scholarly journals The effects of ergot and non-ergot-derived dopamine agonists in an experimental mouse model of endometriosis

Reproduction ◽  
2011 ◽  
Vol 142 (5) ◽  
pp. 745-755 ◽  
Author(s):  
Francisco Delgado-Rosas ◽  
Raúl Gómez ◽  
Hortensia Ferrero ◽  
Francisco Gaytan ◽  
Juan Garcia-Velasco ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Model ◽  
Dopamine Agonists ◽  
Cellular Proliferation ◽  
Lesion Size ◽  
Proliferation Index ◽  
Pilot Studies ◽  
Cardiac Valve Regurgitation ◽  
Angiogenic Gene ◽  
Endothelial Growth Factor

Implantation of a retrogradely shed endometrium during menstruation requires an adequate blood supply, which allows the growth of endometriotic lesions. This suggests that the development of endometriosis can be impaired by inhibiting angiogenesis. The growth of endometriotic foci is impaired by commercial oncological antiangiogenic drugs used to block vascular endothelial growth factor (VEGF) signaling. The dopamine agonist cabergoline (Cb2) inhibits the growth of established endometriosis lesions by exerting antiangiogenic effects through VEGFR2 inactivation. However, the use of ergot-derived Cb2 is associated with an increased incidence of cardiac valve regurgitation. To evaluate the potential usage of non-ergot-derived dopamine agonists for the treatment of human endometriosis, we compared the efficacy of quinagolide with that of Cb2 in preventing angiogenesis and vascularization in a heterologous mouse model of endometriosis. Nude mice whose peritoneum had been implanted with eutopic human endometrial fragments were treated with vehicle, 50 μg/kg per day oral Cb2, or 50 or 200 μg/kg per day quinagolide during a 14-day period. At the end of the treatment period, the implants were excised in order to assess lesion size, cell proliferation, degree of vascularization, and angiogenic gene expression. Neoangiogenesis was inhibited and the size of active endometriotic lesions, cellular proliferation index, and angiogenic gene expression were significantly reduced by both dopamine agonists when compared with the placebo. Given that Cb2 and quinagolide were equally effective in inhibiting angiogenesis and reducing lesion size, these experiments provide the rationale for pilot studies to explore the use of non-ergot-derived dopamine agonists for the treatment of endometriosis in humans.

Immunoassays for the Quantitation of Porcine PAI-1 Antigen and Activity in Biological Fluid Samples

2000 ◽  
Vol 84 (12) ◽  
pp. 1082-1086 ◽  
Author(s):  
Henry M. Leng ◽  
Els Brouwers ◽  
Isabelle Knockaert ◽  
Paul Declerck
Keyword(s):  
Biological Fluid ◽  
Platelet Rich Plasma ◽  
Active Form ◽  
Plasminogen Activator Inhibitor ◽  
Experimental Models ◽  
Activity Levels ◽  
Plasminogen Activator Inhibitor 1 ◽  
Antigen Elisa ◽  
Pathophysiological Role ◽  
Pai 1

SummaryTwo monoclonal antibody-based enzyme-linked immunosorbent assays (ELISAs) for the quantitation of porcine plasminogen activator inhibitor-1 (PAI-1) antigen and activity in plasma were constructed and validated. The intra-assay, interassay, and interdilution coefficients of variation were 4.3, 13, and 8%, respectively, for the antigen ELISA and 5, 16, and 11% for the activity assay. Assay recoveries, in the antigen ELISA, of either latent or active recombinant porcine PAI-1 (10 and 50 ng/ml) added to plasma were 86 ± 9% and 92 ± 22%, respectively, for the latent form and 89 ± 9% and 87 ± 7% for the active form (mean ± SD, n = 3 to 4). In the immunofunctional assay, recoveries for the same concentrations of active PAI-1 were 108 ± 16% and 92 ± 21%, respectively. In male porcine plasma the level of PAI-1 antigen was 31 ± 11 ng/ ml and the activity, 34 ± 16 ng/ml (mean ± SD, n = 10). In female plasma PAI-1 antigen levels were 20 ± 5.2 ng/ml and the PAI-1 activity 42 ± 17 ng/ml (n = 13). A linear correlation was found between PAI-1 antigen and activity levels in male (r = 0.60) and female (r = 0.70) plasma. Immunodepletion resulted in a decrease of >95% of the original PAI-1 antigen or activity levels. Incubation of plasma samples at 37° C for 16 h resulted in a significant decrease (70 to 85%) of PAI-1 activity. Under these conditions (37° C, 16 h) PAI-1 antigen levels remained unchanged in males whereas the response of the female samples in the PAI-1 antigen assay increased two-fold.In lysed platelet-rich plasma males had 990 ± 470 ng/ml antigen and 160 ± 80 ng/ml activity and females, 920 ± 500 ng/ml antigen and 150 ± 98 ng/ml activity corresponding to 2.1 ± 0.77 fg PAI-1 antigen per platelet. Only 16% of PAI-1 released from platelets was found to be active. Linear correlations between PAI-1 antigen and activity were found for both males (r = 0.61) and females (r = 0.67).The assays are both sensitive and specific and may, therefore, aid the elucidation of the pathophysiological role of PAI-1 in swine experimental models of atherosclerosis and other thrombotic disorders.

scholarly journals Protective Role of Reactive Astrocytes in Brain Ischemia

2007 ◽  
Vol 28 (3) ◽  
pp. 468-481 ◽  
Author(s):  
Lizhen Li ◽  
Andrea Lundkvist ◽  
Daniel Andersson ◽  
Ulrika Wilhelmsson ◽  
Nobuo Nagai ◽  
...  
Keyword(s):  
Gap Junctions ◽  
Plasminogen Activator ◽  
Brain Ischemia ◽  
Infarct Volume ◽  
Protective Role ◽  
Experimental Models ◽  
Glutamate Transport ◽  
Reactive Astrocytes ◽  
Plasminogen Activator Inhibitor 1 ◽  
Pai 1

Reactive astrocytes are thought to protect the penumbra during brain ischemia, but direct evidence has been lacking due to the absence of suitable experimental models. Previously, we generated mice deficient in two intermediate filament (IF) proteins, glial fibrillary acidic protein (GFAP) and vimentin, whose upregulation is the hallmark of reactive astrocytes. GFAP−/−Vim−/− mice exhibit attenuated posttraumatic reactive gliosis, improved integration of neural grafts, and posttraumatic regeneration. Seven days after middle cerebral artery (MCA) transection, infarct volume was 210 to 350% higher in GFAP−/−Vim−/− than in wild-type (WT) mice; GFAP−/−, Vim−/− and WT mice had the same infarct volume. Endothelin B receptor (ETBR) immunoreactivity was strong on cultured astrocytes and reactive astrocytes around infarct in WT mice but undetectable in GFAP−/−Vim−/− astrocytes. In WT astrocytes, ETBR colocalized extensively with bundles of IFs. GFAP−/−Vim−/− astrocytes showed attenuated endothelin-3-induced blockage of gap junctions. Total and glutamate transporter-1 (GLT-1)-mediated glutamate transport was lower in GFAP−/−Vim−/− than in WT mice. DNA array analysis and quantitative real-time PCR showed downregulation of plasminogen activator inhibitor-1 (PAI-1), an inhibitor of tissue plasminogen activator. Thus, reactive astrocytes have a protective role in brain ischemia, and the absence of astrocyte IFs is linked to changes in glutamate transport, ETBR-mediated control of gap junctions, and PAI-1 expression.

scholarly journals Pocket Protein-Independent Repression of Urokinase-Type Plasminogen Activator and Plasminogen Activator Inhibitor 1 Gene Expression by E2F1

2000 ◽  
Vol 20 (6) ◽  
pp. 2014-2022 ◽  
Author(s):  
Magdalena Koziczak ◽  
Wilhelm Krek ◽  
Yoshikuni Nagamine
Keyword(s):  
Plasminogen Activator ◽  
Transcriptional Control ◽  
Cellular Proliferation ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Transactivation Domains ◽  
Endogenous Expression ◽  
Expression Of Genes ◽  
Negative Effect ◽  
Pai 1

ABSTRACT Expression of genes of the plasminogen activator (PA) system declines at the G0/G1-S-phase boundary of the cell cycle. We found that overexpression of E2F1-3, which acts mainly in late G1, inhibits promoter activity and endogenous expression of the urokinase-type PA (uPA) and PA inhibitor 1 (PAI-1) genes. This effect is dose dependent and conserved in evolution. Mutation analysis indicated that both the DNA-binding and transactivation domains of E2F1 are necessary for this regulation. Interestingly, an E2F1 mutant lacking the pRB-binding region strongly repressed the uPA and PAI-1 promoters. An E2F-mediated negative effect was also observed in pRB and p107/p130 knockout cell lines. This is the first report that E2F can act as a repressor independently of pocket proteins. Mutation of AP-1 elements in the uPA promoter abrogated E2F-mediated transcriptional inhibition, suggesting the involvement of AP-1 in this regulation. Results shown here identify E2F as an important component of transcriptional control of the PA system and thus provide new insights into mechanisms of cellular proliferation.

943: Plasminogen Activator Inhibitor 1 (PAI-1) is Increased in Human Peyronie's Disease

2005 ◽  
Vol 173 (4S) ◽  
pp. 255-255 ◽  
Author(s):  
Hugo H. Davila ◽  
Thomas R. Magee ◽  
Freddy Zuniga ◽  
Jacob Rajfer ◽  
Nestor F. GonzalezCadavid
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Peyronie’S Disease ◽  
Plasminogen Activator Inhibitor 1 ◽  
Peyronie's Disease ◽  
Activator Inhibitor ◽  
Pai 1

Relationship of Plasminogen Activator Inhibitor-1 Levels following Thrombolytic Therapy with rt-PA as Compared to Streptokinase and Patency of Infarct Related Coronary Artery

1999 ◽  
Vol 82 (07) ◽  
pp. 104-108 ◽  
Author(s):  
Franck Paganelli ◽  
Marie Christine Alessi ◽  
Pierre Morange ◽  
Jean Michel Maixent ◽  
Samuel Lévy ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Thrombolytic Therapy ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Control Group ◽  
Plasminogen Activator Inhibitor 1 ◽  
Vessel Patency ◽  
Activator Inhibitor ◽  
Pai 1

Summary Background: Type 1 plasminogen activator inhibitor (PAI-1) is considered to be risk factor for acute myocardial infarction (AMI). A rebound of circulating PAI-1 has been reported after rt-PA administration. We investigated the relationships between PAI-1 levels before and after thrombolytic therapy with streptokinase (SK) as compared to rt-PA and the patency of infarct-related arteries. Methods and Results: Fifty five consecutive patients with acute MI were randomized to strep-tokinase or rt-PA. The plasma PAI-1 levels were studied before and serially within 24 h after thrombolytic administration. Vessel patency was assessed by an angiogram at 5 ± 1days. The PAI-1 levels increased significantly with both rt-PA and SK as shown by the levels obtained from a control group of 10 patients treated with coronary angioplasty alone. However, the area under the PAI-1 curve was significantly higher with SK than with rt-PA (p <0.01) and the plasma PAI-1 levels peaked later with SK than with rt-PA (18 h versus 3 h respectively). Conversely to PAI-1 levels on admission, the PAI-1 levels after thrombolysis were related to vessel patency. Plasma PAI-1 levels 6 and 18 h after SK therapy and the area under the PAI-1 curve were significantly higher in patients with occluded arteries (p <0.002, p <0.04 and p <0.05 respectively).The same tendency was observed in the t-PA group without reaching significance. Conclusions: This study showed that the PAI-1 level increase is more pronounced after SK treatment than after t-PA treatment. There is a relationship between increased PAI-1 levels after thrombolytic therapy and poor patency. Therapeutic approaches aimed at quenching PAI-1 activity after thrombolysis might be of interest to improve the efficacy of thrombolytic therapy for acute myocardial infarction.

Natriuretic Peptides Regulate the Expression of Tissue Factor and PAI-1 in Endothelial Cells

1999 ◽  
Vol 82 (11) ◽  
pp. 1497-1503 ◽  
Author(s):  
Hajime Tsuji ◽  
Hiromi Nishimura ◽  
Haruchika Masuda ◽  
Yasushi Kunieda ◽  
Hidehiko Kawano ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tissue Factor ◽  
Plasminogen Activator ◽  
Natriuretic Peptide ◽  
Culture Media ◽  
Tissue Type ◽  
Dependent Manner ◽  
Ang Ii ◽  
Plasminogen Activator Inhibitor 1 ◽  
Pai 1

SummaryIn the present study, we demonstrate that brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) interact with angiotensin II (Ang II) in regulative blood coagulation and fibrinolysis by suppressing the expressions of both tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1) induced by Ang II. The expressions of TF and PAI-1 mRNA were analyzed by northern blotting methods, and the activities of TF on the surface of rat aortic endothelial cells (RAECs) and PAI-1 in the culture media were respectively measured by chromogenic assay.Both BNP and CNP suppressed the expressions of TF and PAI-1 mRNA induced by Ang II in a time- and concentration-dependent manner via cGMP cascade, which suppressions were accompanied by respective decrease in activities of TF and PAI-1. However, neither the expression of tissue factor pathway inhibitor (TFPI) nor tissue-type plasminogen activator (TPA) mRNA was affected by the treatment of BNP and CNP.

Fibrinolysis in Normal Subjects - Comparison Between Plasminogen Activator Inhibitor and Other Components of the Fibrinolytic System

1988 ◽  
Vol 59 (02) ◽  
pp. 299-303 ◽  
Author(s):  
Grazia Nicoloso ◽  
Jacques Hauert ◽  
Egbert K O Kruithof ◽  
Guy Van Melle ◽  
Fedor Bachmann
Keyword(s):  
Plasminogen Activator ◽  
Fibrinolytic Activity ◽  
Plasminogen Activator Inhibitor ◽  
Venous Occlusion ◽  
Venous Stasis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Plate Assay ◽  
Fibrin Plate ◽  
Activator Inhibitor ◽  
Pai 1

SummaryWe analyzed fibrinolytic parameters in 20 healthy men and 20 healthy women, aged from 25 to 59, before and after 10 and 20 min venous occlusion. The 10 min post-occlusion fibrinolytic activity measured directly in diluted unfractionated plasma by a highly sensitive 125I-fibrin plate assay correlated well with the activity of euglobulins determined by the classical fibrin plate assay (r = 0.729), but pre-stasis activities determined with these two methods did not correlate (r = 0.084). The enhancement of fibrinolytic activity after venous occlusion was mainly due to an increase of t-PA in the occluded vessels (4-fold increase t-PA antigen after 10 min and 8-fold after 20 min venous occlusion). Plasminogen activator inhibitor (PAI) activity and plasminogen activator inhibitor 1 (PAI-1)1 antigen levels at rest showed considerable dispersion ranging from 1.9 to 12.4 U/ml, respectively 6.9 to 77 ng/ml. A significant increase of PAI-1 antigen levels was observed after 10 and 20 min venous occlusion. At rest no correlation was found between PAI activity or PAI-1 antigen levels and the fibrinolytic activity measured by 125I-FPA. However, a high level of PAI-1 at rest was associated with a high prestasis antigen level of t-PA and a low fibrinolytic response after 10 min of venous stasis. Since the fibrinolytic response inversely correlated with PAI activity at rest, we conclude that its degree depends mainly on the presence of free PAI.

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