scholarly journals Ephs and Ephrins in Adult Endothelial Biology

2020 ◽  
Vol 21 (16) ◽  
pp. 5623 ◽  
Author(s):  
Dianne Vreeken ◽  
Huayu Zhang ◽  
Anton Jan van Zonneveld ◽  
Janine M. van Gils
Keyword(s):  
Endothelial Cells ◽  
Endothelial Function ◽  
Vascular Development ◽  
Vascular Biology ◽  
Protein Family ◽  
Tissue Homeostasis ◽  
Leukocyte Recruitment ◽  
Eph Receptors ◽  
Ephrin Ligands

Eph receptors and their ephrin ligands are important guidance molecules during neurological and vascular development. In recent years, it has become clear that the Eph protein family remains functional in adult physiology. A subset of Ephs and ephrins is highly expressed by endothelial cells. As endothelial cells form the first barrier between the blood and surrounding tissues, maintenance of a healthy endothelium is crucial for tissue homeostasis. This review gives an overview of the current insights of the role of ephrin ligands and receptors in endothelial function and leukocyte recruitment in the (patho)physiology of adult vascular biology.

scholarly journals Emerging Role of AP-1 Transcription Factor JunB in Angiogenesis and Vascular Development

2021 ◽  
Vol 22 (6) ◽  
pp. 2804
Author(s):  
Yasuo Yoshitomi ◽  
Takayuki Ikeda ◽  
Hidehito Saito-Takatsuji ◽  
Hideto Yonekura
Keyword(s):  
Endothelial Cells ◽  
Transcription Factor ◽  
Blood Vessel ◽  
Vascular Endothelial Cells ◽  
Vascular Development ◽  
Endothelial Cell Migration ◽  
Vascular Endothelial ◽  
Blood Vessel Formation ◽  
Vessel Formation

Blood vessels are essential for the formation and maintenance of almost all functional tissues. They play fundamental roles in the supply of oxygen and nutrition, as well as development and morphogenesis. Vascular endothelial cells are the main factor in blood vessel formation. Recently, research findings showed heterogeneity in vascular endothelial cells in different tissue/organs. Endothelial cells alter their gene expressions depending on their cell fate or angiogenic states of vascular development in normal and pathological processes. Studies on gene regulation in endothelial cells demonstrated that the activator protein 1 (AP-1) transcription factors are implicated in angiogenesis and vascular development. In particular, it has been revealed that JunB (a member of the AP-1 transcription factor family) is transiently induced in endothelial cells at the angiogenic frontier and controls them on tip cells specification during vascular development. Moreover, JunB plays a role in tissue-specific vascular maturation processes during neurovascular interaction in mouse embryonic skin and retina vasculatures. Thus, JunB appears to be a new angiogenic factor that induces endothelial cell migration and sprouting particularly in neurovascular interaction during vascular development. In this review, we discuss the recently identified role of JunB in endothelial cells and blood vessel formation.

scholarly journals MicroRNA as Crucial Regulators of Gene Expression in Estradiol-Treated Human Endothelial Cells

2018 ◽  
Vol 45 (5) ◽  
pp. 1878-1892 ◽  
Author(s):  
Xavier Vidal-Gómez ◽  
Daniel Pérez-Cremades ◽  
Ana Mompeón ◽  
Ana Paula Dantas ◽  
Susana Novella ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Endothelial Function ◽  
Pathway Analysis ◽  
Mirna Expression ◽  
Umbilical Vein ◽  
Mirna Gene ◽  
Mirna Profile ◽  
Human Endothelial Cells ◽  
Estrogen Regulation

Background/Aims: Estrogen signalling plays an important role in vascular biology as it modulates vasoactive and metabolic pathways in endothelial cells. Growing evidence has also established microRNA (miRNA) as key regulators of endothelial function. Nonetheless, the role of estrogen regulation on miRNA profile in endothelial cells is poorly understood. In this study, we aimed to determine how estrogen modulates miRNA profile in human endothelial cells and to explore the role of the different estrogen receptors (ERα, ERβ and GPER) in the regulation of miRNA expression by estrogen. Methods: We used miRNA microarrays to determine global miRNA expression in human umbilical vein endothelial cells (HUVEC) exposed to a physiological concentration of estradiol (E2; 1 nmol/L) for 24 hours. miRNA-gene interactions were computationally predicted using Ingenuity Pathway Analysis and changes in miRNA levels were validated by qRT-PCR. Role of ER in the E2-induced miRNA was additionally confirmed by using specific ER agonists and antagonists. Results: miRNA array revealed that expression of 114 miRNA were significantly modified after E2 exposition. Further biological pathway analysis revealed cell death and survival, lipid metabolism, reproductive system function, as the top functions regulated by E2. We validated changes in the most significantly increased (miR-30b-5p, miR-487a-5p, miR-4710, miR-501-3p) and decreased (miR-378h and miR-1244) miRNA and the role of ER in these E2-induced miRNA was determined. Results showed that both classical, ERα and ERβ, and membrane-bound ER, GPER, differentially regulated specific miRNA. In silico analysis of validated miRNA promoters identified specific ER binding sites. Conclusion: Our findings identify differentially expressed miRNA pathways linked to E2 in human endothelial cells through ER, and provide new insights by which estrogen can modulate endothelial function.

Abstract 18705: BRCA2 is a Novel Regulator of Endothelial Cell Function and Apoptosis

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Pratiek N Matkar ◽  
Wei J Cao ◽  
Mohammed Al-Omran ◽  
Subodh Verma ◽  
Howard Leong-Poi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Endothelial Cells ◽  
Endothelial Function ◽  
Dna Damage Repair ◽  
Genotoxic Stress ◽  
Tube Formation ◽  
Protein Levels ◽  
Damage Repair

Background: Germ-line mutations in the tumor suppressor gene BRCA2 (breast cancer 2, early onset) predispose carriers not only to breast cancer, but also to other cancers. BRCA2 plays crucial role in the genome integrity maintenance and is central to DNA-damage repair. BRCA2-associated DNA-damage responses are not only specific to cancer syndromes but also represent a common pathophysiological basis for diverse cardiovascular diseases (CVDs). These observations led us to hypothesize that BRCA2 is an essential regulator of endothelial function and apoptosis following genotoxic stress. Methods: To elucidate the role of BRCA2 in endothelial cells, we silenced BRCA2 in the human umbilical vein endothelial cells (ECs) and measured the indices of EC function; tube formation and proliferation, DNA-damage/repair and apoptosis by qPCR, immunoblotting and immunofluorescence following doxorubicin (Dox) treatment. Results: We confirmed the basal expression and successful silencing of BRCA2 in ECs at transcript and protein levels by qPCR and immunoblotting, respectively. Genotoxic stress in the form of Dox exacerbated DNA-damage in BRCA2-silenced ECs as evident by increased expression and activation of DNA double-stranded breaks (DSBs) marker H2A.X and reduced RAD51-foci formation, an essential regulator of DSB repair. Increased DSBs were associated with significantly increased expression and activation of p53, and increased expression of p53-upregulated modulator of apoptosis PUMA. Elevated levels of DNA-damage and p53 were further associated with significantly increased Dox-induced apoptosis in BRCA2-silenced ECs as measured by immunoblotting for cleaved-caspase-3 and TUNEL-staining.Key indices of endothelial function, including tube formation and proliferation, were significantly reduced following Dox-treatment in BRCA2-deficient ECs, which was accompanied with significantly increased expression of cell cycle inhibitor, p21 at transcript and protein levels. Conclusion: Our data for the first time, show an entirely novel role of BRCA2 as a regulator of endothelium, and provide important clues regarding a potential susceptibility of BRCA2 mutation carriers to anthracycline-induced CVDs, a cornerstone of chemotherapy for cancer.

scholarly journals Evaluation of the Anti-Tumor Activity of Small Molecules Targeting Eph/Ephrins in APC min/J Mice

2020 ◽  
Vol 13 (4) ◽  
pp. 69
Author(s):  
Miriam Corrado ◽  
Carmine Giorgio ◽  
Elisabetta Barocelli ◽  
Giuseppe Vittucci Marzetti ◽  
Anna Maria Cantoni ◽  
...  
Keyword(s):  
Small Molecules ◽  
Tyrosine Kinases ◽  
Tumor Development ◽  
Eph Receptors ◽  
Pharmacological Approach ◽  
Ephrin Ligands ◽  
Prevent Tumor Growth ◽  
First Time ◽  
Anti Tumor Activity

The Eph receptors are the largest receptors tyrosine kinases (RTKs) family in humans and together with ephrin ligands constitute a complex cellular communication system often dysregulated in many tumors. The role of the Eph-ephrin system in colorectal cancer (CRC) has been investigated and different expression of Eph receptors have been associated with tumor development and progression. In light of this evidence, we investigated if a pharmacological approach aimed at inhibiting Eph/ephrin interaction through small molecules could prevent tumor growth in APC min/J mice. The 8-week treatment with the Eph-ephrin antagonist UniPR129 significantly reduced the number of adenomas in the ileum and decreased the diameter of adenomas in the same region. Overall our data suggested as UniPR129 could be able to slow down the tumor development in APC min/J mice. These results further confirm literature data about Eph kinases as a new valuable target in the intestinal cancer and for the first time showed the feasibility of the Eph-ephrin inhibition as a useful pharmacological approach against the intestinal tumorigenesis. In conclusion this work paves the way for further studies with Eph-ephrin inhibitors in order to confirm the Eph antagonism as innovative pharmacological approach with preventive benefit in the intestinal tumor development.

scholarly journals The Role of TRPM2 in Endothelial Function and Dysfunction

2021 ◽  
Vol 22 (14) ◽  
pp. 7635
Author(s):  
Wioletta Zielińska ◽  
Jan Zabrzyński ◽  
Maciej Gagat ◽  
Alina Grzanka
Keyword(s):  
Endothelial Cells ◽  
Endothelial Function ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Sequence Motif ◽  
Attractive Therapeutic Target ◽  
Transient Receptor

The transient receptor potential (TRP) melastatin-like subfamily member 2 (TRPM2) is a non-selective calcium-permeable cation channel. It is expressed by many mammalian tissues, including bone marrow, spleen, lungs, heart, liver, neutrophils, and endothelial cells. The best-known mechanism of TRPM2 activation is related to the binding of ADP-ribose to the nudix-box sequence motif (NUDT9-H) in the C-terminal domain of the channel. In cells, the production of ADP-ribose is a result of increased oxidative stress. In the context of endothelial function, TRPM2-dependent calcium influx seems to be particularly interesting as it participates in the regulation of barrier function, cell death, cell migration, and angiogenesis. Any impairments of these functions may result in endothelial dysfunction observed in such conditions as atherosclerosis or hypertension. Thus, TRPM2 seems to be an attractive therapeutic target for the conditions connected with the increased production of reactive oxygen species. However, before the application of TRPM2 inhibitors will be possible, some issues need to be resolved. The main issues are the lack of specificity, poor membrane permeabilization, and low stability in in vivo conditions. The article aims to summarize the latest findings on a role of TRPM2 in endothelial cells. We also show some future perspectives for the application of TRPM2 inhibitors in cardiovascular system diseases.

scholarly journals The Role of the Eph Receptor Family in Tumorigenesis

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 206
Author(s):  
Meg Anderton ◽  
Emma van der Meulen ◽  
Melissa J. Blumenthal ◽  
Georgia Schäfer
Keyword(s):  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Signalling Pathways ◽  
Cancer Therapies ◽  
Eph Receptors ◽  
Eph Receptor ◽  
Ephrin Ligands ◽  
And Migration ◽  
Receptor Family

The Eph receptor tyrosine kinase family, activated by binding to their cognate ephrin ligands, are important components of signalling pathways involved in animal development. More recently, they have received significant interest due to their involvement in oncogenesis. In most cases, their expression is altered, affecting the likes of cell proliferation and migration. Depending on the context, Eph receptors have the potential to act as both tumour promoters and suppressors in a number of cancers, such as breast cancer, colorectal cancer, lung cancer, prostate cancer, brain cancer and Kaposi’s sarcoma (KS), the latter being intrinsically linked to EphA2 as this is the receptor used for endothelial cell entry by the Kaposi’s sarcoma-associated herpesvirus (KSHV). In addition, EphA2 deregulation is associated with KS, indicating that it has a dual role in this case. Associations between EphA2 sequence variation and KSHV infection/KS progression have been detected, but further work is required to formally establish the links between EphA2 signalling and KS oncogenesis. This review consolidates the available literature of the role of the Eph receptor family, and particularly EphA2, in tumorigenesis, with the aim to develop a better understanding of Eph signalling pathways for potential targeting in novel cancer therapies.

scholarly journals Flow-through isolation of human first trimester umbilical cord endothelial cells

2021 ◽  
Author(s):  
Michael Gruber ◽  
Elisa Weiss ◽  
Monika Siwetz ◽  
Ursula Hiden ◽  
Martin Gauster
Keyword(s):  
Endothelial Cells ◽  
Endothelial Function ◽  
Umbilical Vein ◽  
Vascular Development ◽  
First Trimester ◽  
Adverse Conditions ◽  
Endothelial Colony Forming Cells ◽  
Flow Through ◽  
In Pregnancy

AbstractHuman umbilical vein and artery endothelial cells (HUVEC; HUAEC), placental endothelial cells (fpAEC), and endothelial colony-forming cells (ECFC) from cord blood are a widely used model for researching placental vascular development, fetal and placental endothelial function, and the effect of adverse conditions in pregnancy thereon. However, placental vascular development and angiogenesis start in the first weeks of gestation, and adverse conditions in pregnancy may also affect endothelial function before term, suggesting that endothelial cells from early pregnancy may respond differently. Thus, we established a novel, gentle flow-through method to isolate pure human umbilical endothelial cells from first trimester (FTUEC). FTUEC were characterized and their phenotype was compared to the umbilical endothelium in situ as well as to other fetal endothelial cell models from term of gestation, i.e. HUVEC, fpAEC, ECFC. FTUEC possess a CD34-positive, juvenile endothelial phenotype, and can be expanded and passaged. We regard FTUEC as a valuable tool to study developmental processes as well as the effect of adverse insults in pregnancy in vitro.

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