scholarly journals Evidence-Based View of Safety and Effectiveness of Prokineticin Receptors Antagonists during Pregnancy

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 309
Author(s):  
Deborah Reynaud ◽  
Frederic Sergent ◽  
Roland Abi Nahed ◽  
Wael Traboulsi ◽  
Constance Collet ◽  
...  
Keyword(s):  
Pregnancy Outcome ◽  
Normal Pregnancy ◽  
G Protein Coupled Receptors ◽  
Endocrine Gland ◽  
Vascular Endothelial ◽  
Aberrant Expression ◽  
Vegf Signaling ◽  
Improve Pregnancy Outcome ◽  
Endothelial Growth Factor ◽  
G Protein Coupled

Endocrine gland derived vascular endothelial growth factor (EG-VEGF) is a canonical member of the prokineticin (PROKs) family. It acts via the two G-protein coupled receptors, namely PROKR1 and PROKR2. We have recently demonstrated that EG-VEGF is highly expressed in the human placenta; contributes to placental vascularization and growth and that its aberrant expression is associated with pregnancy pathologies including preeclampsia and fetal growth restriction. These findings strongly suggested that antagonization of its receptors may constitute a potential therapy for the pregnancy pathologies. Two specific antagonists of PROKR1 (PC7) and for PROKR2 (PKRA) were reported to reverse PROKs adverse effects in other systems. In the view of using these antagonists to treat pregnancy pathologies, a proof of concept study was designed to determine the biological significances of PC7 and PKRA in normal pregnancy outcome. PC7 and PKRA were tested independently or in combination in trophoblast cells and during early gestation in the gravid mouse. Both independent and combined treatments uncovered endogenous functions of EG-VEGF. The independent use of antagonists distinctively identified PROKR1 and PROKR2-mediated EG-VEGF signaling on trophoblast differentiation and invasion; thereby enhancing feto-placental growth and pregnancy outcome. Thus, our study provides evidence for the potential safe use of PC7 or PKRA to improve pregnancy outcome.

scholarly journals Endothelins and hypoxia-inducible factor in cancer

2007 ◽  
Vol 14 (2) ◽  
pp. 233-244 ◽  
Author(s):  
M J Grimshaw
Keyword(s):  
Hypoxia Inducible Factor ◽  
Tumour Microenvironment ◽  
G Protein Coupled Receptors ◽  
Vascular Endothelial ◽  
Small Peptides ◽  
Tumour Type ◽  
Endothelin System ◽  
Endothelial Growth Factor ◽  
G Protein Coupled ◽  
Made In

The endothelin system is a family of three similar small peptides, two G-protein-coupled receptors and two proteinases. Endothelins have several physiological roles, notably in embryonic differentiation and vascular homeostasis. Numerous types of tumour express endothelins and their regulation is often aberrant when compared with the normal tissue from which the tumour arose. However, endothelin expression is tumour-type specific, and in some instances, expression of individual members of the endothelin system will be upregulated, while in other tumour types, they may be downregulated. Endothelins have numerous potential roles in tumours including modulating angiogenesis, inducing mitogenesis and invasion of tumour cells, and protecting cells from apoptosis. Expression of endothelins is controlled by the tumour microenvironment, whilst the endothelins themselves modify that environment; a case in point is that hypoxia stimulates endothelin expression via hypoxia-inducible factor (HIF)-1, while endothelins stabilise HIF-1 leading to expression of, for instance, vascular endothelial growth factor. This review highlights the potential roles of endothelins in various cancers and describes the pre-clinical and clinical progress that has been made in several tumour types – notably prostate, ovary, melanoma and breast cancer. The interactions between the endothelin network and HIF-1 are highlighted.

scholarly journals Endocrine gland-derived vascular endothelial growth factor in rat pancreas: genetic expression and testosterone regulation

2008 ◽  
Vol 197 (2) ◽  
pp. 309-314 ◽  
Author(s):  
Angélica Morales ◽  
Sumiko Morimoto ◽  
Lorenza Díaz ◽  
Guillermo Robles ◽  
Vicente Díaz-Sánchez
Keyword(s):  
Gene Expression ◽  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Pancreatic Tissue ◽  
Endocrine Gland ◽  
Vascular Endothelial ◽  
Rinm5f Cells ◽  
Vegf Gene ◽  
Rat Pancreas ◽  
Endothelial Growth Factor

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an endothelial cell mitogen, expressed essentially in steroidogenic cells. Recently, the expression of EG-VEGF in normal human pancreas and pancreatic adenocarcinoma has been demonstrated. Epidemiologically, pancreatic carcinogenesis is more frequent in males than females, and given that androgen receptors and testosterone biotransformation have been described in pancreas, we hypothesized that testosterone could participate in the regulation of EG-VEGF expression. In this study, we investigated the regulation of EG-VEGF gene expression by testosterone in normal rat pancreatic tissue and rat insulinoma cells (RINm5F). Total RNA was extracted from rat pancreas and cultured cells. Gene expression was studied by real-time PCR and protein detection by immunohistochemistry. Serum testosterone was quantified by RIA. Results showed that EG-VEGF is expressed predominantly in pancreatic islets and vascular endothelium, as well as in RINm5F cells. EG-VEGF gene expression was lower in the pancreas of rats with higher testosterone serum levels. A similar effect that was reverted by flutamide was observed in testosterone-treated RINm5F cells. In summary, testosterone down-regulated EG-VEGF gene expression in rat pancreatic tissue and RINm5F cells. This effect could be mediated by the androgen receptor. To our knowledge, this is the first time that a direct effect of testosterone on EG-VEGF gene expression in rat pancreas and RINm5F cells is demonstrated.

scholarly journals Scl isoforms act downstream of etsrp to specify angioblasts and definitive hematopoietic stem cells

Blood ◽  
2010 ◽  
Vol 115 (26) ◽  
pp. 5338-5346 ◽  
Author(s):  
Xi Ren ◽  
Gustavo A. Gomez ◽  
Bo Zhang ◽  
Shuo Lin
Keyword(s):  
Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Critical Role ◽  
Vascular Endothelial ◽  
Hematopoietic Stem ◽  
Vegf Signaling ◽  
Endothelial Growth Factor ◽  
Endothelial Development ◽  
Definitive Hematopoiesis ◽  
Runx1 Expression

Abstract Recent lineage studies suggest that hematopoietic stem cells (HSCs) may be derived from endothelial cells. However, the genetic hierarchy governing the emergence of HSCs remains elusive. We report here that zebrafish ets1-related protein (etsrp), which is essential for vascular endothelial development, also plays a critical role in the initiation of definitive hematopoiesis by controlling the expression of 2 stem cell leukemia (scl) isoforms (scl-α and scl-β) in angioblasts. In etsrp morphants, which are deficient in endothelial and HSC development, scl-α alone partially rescues angioblast specification, arterial-venous differentiation, and the expression of HSC markers, runx1 and c-myb, whereas scl-β requires angioblast rescue by fli1a to restore runx1 expression. Interestingly, when vascular endothelial growth factor (Vegf) signaling is inhibited, HSC marker expression can still be restored by scl-α in etsrp morphants, whereas the rescue of arterial ephrinb2a expression is blocked. Furthermore, both scl isoforms partially rescue runx1 but not ephrinb2a expression in embryos deficient in Vegf signaling. Our data suggest that downstream of etsrp, scl-α and fli1a specify the angioblasts, whereas scl-β further initiates HSC specification from this angioblast population, and that Vegf signaling acts upstream of scl-β during definitive hematopoiesis.

scholarly journals Convergence of VEGF and YAP/TAZ signaling: Implications for angiogenesis and cancer biology

2018 ◽  
Vol 11 (552) ◽  
pp. eaau1165 ◽  
Author(s):  
Ameer L. Elaimy ◽  
Arthur M. Mercurio
Keyword(s):  
Endothelial Cells ◽  
Tumor Cells ◽  
Cancer Biology ◽  
Vascular Endothelial ◽  
Vascular Growth ◽  
Vegf Signaling ◽  
Pathological Angiogenesis ◽  
Cytoskeletal Dynamics ◽  
Rho Family ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) stimulates endothelial cells to promote both developmental and pathological angiogenesis. VEGF also directly affects tumor cells and is associated with the initiation, progression, and recurrence of tumors, as well as the emergence and maintenance of cancer stem cells (CSCs). Studies have uncovered the importance of the transcriptional regulators YAP and TAZ in mediating VEGF signaling. For example, VEGF stimulates the GTPase activity of Rho family members and thereby alters cytoskeletal dynamics, which contributes to the activation of YAP and TAZ. In turn, YAP- and TAZ-mediated changes in gene expression sustain Rho family member activity and cytoskeletal effects to promote both vascular growth and remodeling in endothelial cells and the acquisition of stem-like traits in tumor cells. In this Review, we discuss how these findings further explain the pathophysiological roles of VEGF and YAP/TAZ, identify their connections to other receptor-mediated pathways, and reveal ways of therapeutically targeting their convergent signals in patients.

Characterization of the vasculogenic block in the absence of vascular endothelial growth factor-A

Blood ◽  
2000 ◽  
Vol 95 (6) ◽  
pp. 1979-1987 ◽  
Author(s):  
Victoria L. Bautch ◽  
Sambra D. Redick ◽  
Aaron Scalia ◽  
Marco Harmaty ◽  
Peter Carmeliet ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Embryonic Stem ◽  
Dependent Manner ◽  
Vascular Endothelial ◽  
Vegf Signaling ◽  
Homozygous Mutant ◽  
Endothelial Growth Factor ◽  
Rna Levels

Abstract Vascular endothelial growth factor (VEGF) signaling is required for both differentiation and proliferation of vascular endothelium. Analysis of differentiated embryonic stem cells with one or both VEGF-A alleles deleted showed that both the differentiation and the expansion of endothelial cells are blocked during vasculogenesis. Blood island formation was reduced by half in hemizygous mutant VEGF cultures and by 10-fold in homozygous mutant VEGF cultures. Homozygous mutant cultures could be partially rescued by the addition of exogenous VEGF. RNA levels for the endothelial adhesion receptors ICAM-2 and PECAM were reduced in homozygous mutant cultures, but ICAM-2 RNA levels decreased substantially, whereas PECAM RNA levels remained at hemizygous levels. The quantitative data correlated with the antibody staining patterns because cells that were not organized into vessels expressed PECAM but not ICAM-2. These PECAM+ cell clumps accumulated in mutant cultures as vessel density decreased, suggesting that they were endothelial cell precursors blocked from maturation. A subset of PECAM+ cells in clumps expressed stage-specific embryonic antigen-1 (SSEA-1), and all were ICAM-2(−) and CD34(−), whereas vascular endothelial cells incorporated into vessels were PECAM(+), ICAM-2(+), CD34(+), and SSEA-1(−). Analysis of flk-1 expression indicated that a subset of vascular precursor cells coexpressed PECAM and flk-1. These data suggest that VEGF signaling acts in a dose-dependent manner to affect both a specific differentiation step and the subsequent expansion of endothelial cells.

scholarly journals VEGF expands erythropoiesis via hypoxia-independent induction of erythropoietin in noncanonical perivascular stromal cells

2018 ◽  
Vol 216 (1) ◽  
pp. 215-230 ◽  
Author(s):  
Alissa C. Greenwald ◽  
Tamar Licht ◽  
Saran Kumar ◽  
Sunday S. Oladipupo ◽  
Seema Iyer ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Vascular Endothelial Growth Factor ◽  
Smooth Muscle ◽  
Stem Cell ◽  
Stromal Cells ◽  
Vascular Endothelial ◽  
Erythroid Progenitor ◽  
Vegf Signaling ◽  
Kidney Liver ◽  
Endothelial Growth Factor

Insufficient erythropoiesis due to increased demand is usually met by hypoxia-driven up-regulation of erythropoietin (Epo). Here, we uncovered vascular endothelial growth factor (VEGF) as a novel inducer of Epo capable of increasing circulating Epo under normoxic, nonanemic conditions in a previously unrecognized reservoir of Epo-producing cells (EPCs), leading to expansion of the erythroid progenitor pool and robust splenic erythropoiesis. Epo induction by VEGF occurs in kidney, liver, and spleen in a population of Gli1+SMA+PDGFRβ+ cells, a signature shared with vascular smooth muscle cells (VSMCs) derived from mesenchymal stem cell–like progenitors. Surprisingly, inhibition of PDGFRβ signaling, but not VEGF signaling, abrogated VEGF-induced Epo synthesis. We thus introduce VEGF as a new player in Epo induction and perivascular Gli1+SMA+PDGFRβ+ cells as a previously unrecognized EPC reservoir that could be harnessed for augmenting Epo synthesis in circumstances such as chronic kidney disease where production by canonical EPCs is compromised.

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