scholarly journals Evaluation of lung VEGF-A transduction during hyperoxia-induced injury in rats

2018 ◽  
Author(s):  
William Raoul ◽  
Vanessa Louzier ◽  
Saadia Eddahibi ◽  
Serge Adnot ◽  
Bernard Maitre ◽  
...  
Keyword(s):  
Endothelial Cell Proliferation ◽  
High Dose ◽  
Marginal Effect ◽  
Hyperoxic Exposure ◽  
Viral Particles ◽  
Endothelial Proliferation ◽  
Diffuse Loss ◽  
Capillary Bed ◽  
Fraction Of Inspired Oxygen ◽  
Endothelial Growth Factor

AbstractBackgroundSince Vascular Endothelial Growth Factor (VEGF) is a main factor for endothelial survival, we evaluated whether VEGF transduction could ameliorate hyperoxia induced injury, which is associated with predominant endothelial injury.Methods and ResultsTransduction (induced 48 hours before hyperoxic exposure) using adenoviral vector (Ad.) for VEGF (1010 viral particles [VP]) increased moderately survival under hyperoxia (fraction of inspired oxygen [FIO2] >95%) as compared with Ad.Null (1010 VP) transduction, whereas VEGF transduction with a lower dose (5.109 VP) had no effect. After 48 hours of hyperoxia, Ad.VEGF transduction increased lung VEGF concentration, prevented the diffuse loss of capillary bed and induced patchy areas of endothelial cell proliferation (CD31 immunostaining) with interstitial inflammatory cell recruitment as compared to Ad. Null transduction. Hyperoxia was associated with diffuse apoptosis that was inhibited only in patchy areas of endothelial proliferation under VEGF transduction. Hyperoxia-induced alveolar inflammation was similar with Ad.Null and Ad.VEGF. Under normoxia, the high dose of VEGF transduction induced diffuse alveolar inflammation whereas the low dose did not suggesting a pro-inflammatory effect of VEGF that may have participated to increased survival under hyperoxia.ConclusionsWe demonstrate that lung VEGF-A transduction despite inhibition of the loss of capillary bed has a marginal effect of on animal survival during hyperoxia-induced injury.

scholarly journals Correlation of endothelial cell proliferation with vascular endothelial growth factor in endometrium of women with menorrhagia

2017 ◽  
Vol 5 (5) ◽  
pp. 2034
Author(s):  
Kiran B. Mehra ◽  
Nitin M. Gangane ◽  
Deepti R. Joshi
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Cell Proliferation ◽  
Endothelial Cell Proliferation ◽  
P Value ◽  
Vascular Endothelial ◽  
Luminal Surface ◽  
Vegf Expression ◽  
Secretory Phase ◽  
Endothelial Proliferation ◽  
Endothelial Growth Factor

Background: Approximately 30% of women of reproductive age experience excessive blood loss during menstruation. In 50% of cases, menorrhagia has no underlying pathology. However, until recently, the only permanent cure for menorrhagia was hysterectomy. In this study we aim to determine the correlation of vascular endothelial growth factor (VEGF) expression with markers of endometrial endothelial cell proliferation like proliferating cell nuclear antigen (PCNA) and Cluster Determination (CD34).Methods: A total of 100 patients with history of menorrhagia were selected for study. Double Immunohistochemistry was performed on these endometrial biopsy sections. Proliferating endothelial cells were identified by an immunohistochemical double staining technique with PCNA and CD34. VEGF expression was also seen in endometrial biopsy.Results: In general, expression of both VEGF and PCNA was more in functional layer than basal layer in both menorrhagic patients as well as non menorrhagic patients.  When glandular cytoplasmic VEGF expression was compared with PCNA the association was statistically significant whereas completely opposite findings was seen with glandular luminal surface VEGF positivity but the association was statistically significant. In secretory phase (p-value<0.001) there was highly statistically significant association in PCNA grading with glandular luminal surface VEGF positivity whereas when we correlated PCNA with  cytoplasmic  glandular VEGF in secretory phase it was statistically significant (p-value<0.001).Conclusions: The endothelial proliferation was significantly higher in menorrhagia patients during late secretory phase of cycle than controls. We were able to demonstrate increased endothelial proliferation in patients in the premenstrual part of cycle.

scholarly journals The VEGF receptor Flt-1 spatially modulates Flk-1 signaling and blood vessel branching

2008 ◽  
Vol 181 (5) ◽  
pp. 847-858 ◽  
Author(s):  
Nicholas C. Kappas ◽  
Gefei Zeng ◽  
John C. Chappell ◽  
Joseph B. Kearney ◽  
Surovi Hazarika ◽  
...  
Keyword(s):  
Blood Vessel ◽  
Embryonic Stem ◽  
Branching Morphogenesis ◽  
Endothelial Cell Proliferation ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Endothelial Proliferation ◽  
Integrated Regulation ◽  
Set Up ◽  
Endothelial Growth Factor

Blood vessel formation requires the integrated regulation of endothelial cell proliferation and branching morphogenesis, but how this coordinated regulation is achieved is not well understood. Flt-1 (vascular endothelial growth factor [VEGF] receptor 1) is a high affinity VEGF-A receptor whose loss leads to vessel overgrowth and dysmorphogenesis. We examined the ability of Flt-1 isoform transgenes to rescue the vascular development of embryonic stem cell–derived flt-1−/− mutant vessels. Endothelial proliferation was equivalently rescued by both soluble (sFlt-1) and membrane-tethered (mFlt-1) isoforms, but only sFlt-1 rescued vessel branching. Flk-1 Tyr-1173 phosphorylation was increased in flt-1−/− mutant vessels and partially rescued by the Flt-1 isoform transgenes. sFlt-1–rescued vessels exhibited more heterogeneous levels of pFlk than did mFlt-1–rescued vessels, and reporter gene expression from the flt-1 locus was also heterogeneous in developing vessels. Our data support a model whereby sFlt-1 protein is more efficient than mFlt-1 at amplifying initial expression differences, and these amplified differences set up local discontinuities in VEGF-A ligand availability that are important for proper vessel branching.

scholarly journals Mid-luteal angiogenesis and function in the primate is dependent on vascular endothelial growth factor

2001 ◽  
Vol 168 (3) ◽  
pp. 409-416 ◽  
Author(s):  
SE Dickson ◽  
R Bicknell ◽  
HM Fraser
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Growth Factor ◽  
Luteal Phase ◽  
Smooth Muscle Actin ◽  
Proliferation Index ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor

Vascular endothelial growth factor (VEGF) is essential for the angiogenesis required for the formation of the corpus luteum; however, its role in ongoing luteal angiogenesis and in the maintenance of the established vascular network is unknown. The aim of this study was to determine whether VEGF inhibition could intervene in ongoing luteal angiogenesis using immunoneutralisation of VEGF starting in the mid-luteal phase. In addition, the effects on endothelial cell survival and the recruitment of periendothelial support cells were examined. Treatment with a monoclonal antibody to VEGF, or mouse gamma globulin for control animals, commenced on day 7 after ovulation and continued for 3 days. Bromodeoxyuridine (BrdU), used to label proliferating cells to obtain a proliferation index, was administered one hour before collecting ovaries from control and treated animals. Ovarian sections were stained using antibodies to BrdU, the endothelial cell marker, CD31, the pericyte marker, alpha-smooth muscle actin, and 3' end DNA fragments as a marker for apoptosis. VEGF immunoneutralisation significantly suppressed endothelial cell proliferation and the area occupied by endothelial cells while increasing pericyte coverage and the incidence of endothelial cell apoptosis. Luteal function was markedly compromised by anti-VEGF treatment as judged by a 50% reduction in plasma progesterone concentration. It is concluded that ongoing angiogenesis in the mid-luteal phase is primarily driven by VEGF, and that a proportion of endothelial cells of the mid-luteal phase vasculature are dependent on VEGF support.

Abstract 18332: EphrinB2/EphB4 Signaling controls the Dose-Dependent Switch between Normal and Aberrant Angiogenesis by VEGF

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Elena Groppa ◽  
Veronica Sacchi ◽  
Sime Brkic ◽  
Marianna Trani ◽  
Michael Heberer ◽  
...  
Keyword(s):  
Growth Factor ◽  
Longitudinal Splitting ◽  
Vascular Growth ◽  
Over Expression ◽  
Capillary Networks ◽  
Endothelial Proliferation ◽  
Mouse Limb ◽  
Normal Networks ◽  
Endothelial Growth Factor

Vascular Endothelial Growth Factor-A (VEGF) is the master regulator of vascular growth and it can induce either normal or aberrant angiogenesis depending on its dose in the microenvironment around each producing cell in vivo, and not on the total amount. However, stimulation of pericyte recruitment by co-expression of Platelet Derived Growth Factor-BB (PDGF-BB) could prevent aberrant structures despite heterogeneous and high VEGF levels and switch to homogeneously normal angiogenesis. Here we dissected the role of specific pericyte-mediated signaling pathways in the switch between normal and aberrant angiogenesis by VEGF. Monoclonal populations of transduced myoblasts were used to homogeneously express specific VEGF doses, inducing either normal or aberrant angiogenesis, and were further transduced to secrete soluble blockers of the TGFβ-1/TGFβ-R, Tie2/Angiopoietin or EphB4/EphrinB2 pathways (LAP, sTie2Fc and sEphB4, respectively). Two weeks after implantation into mouse limb muscles, neither TGFβ nor Angiopoietin blockade altered the normal angiogenesis by low VEGF, whereas EphrinB2/EphB4 inhibition caused a switch to aberrant angioma-like structures, similar to the effects of blocking pericyte recruitment. Conversely, gain-of-function of EphB4 signaling by systemic treatment with recombinant EphrinB2-Fc completely prevented aberrant angiogenesis by high VEGF levels and yielded normal networks of mature capillaries. We recently found that VEGF over-expression in muscle induces angiogenesis without sprouting, but by circumferential enlargement and longitudinal splitting (intussusception). EphB4 inhibition increased both endothelial proliferation and the diameter of initial enlargements induced by low VEGF (4 days), leading to a failure of splitting and progressive angioma growth. However, it did not interfere with pericyte recruitment, contrary to high VEGF alone. Conversely, EphB4 stimulation decreased both endothelial proliferation and the diameter of enlargements induced by high VEGF to values similar to low VEGF alone, and accelerated splitting into pericyte-covered capillary networks. In conclusion, EphrinB2/EphB4 signaling can prevent VEGF-induced aberrant angiogenesis by regulating intussusception.

Notch2 Suppression Mimicking Changes in Human Pulmonary Hypertension Modulates Notch1 and Promotes Endothelial Cell Proliferation

2021 ◽  
Author(s):  
Sanghamitra Sahoo ◽  
Yao Li ◽  
Daniel de Jesus ◽  
John Charles Sembrat II ◽  
Mauricio M Rojas ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Target Genes ◽  
Pulmonary Arteries ◽  
Notch Receptor ◽  
Endothelial Cell Proliferation ◽  
Tissue Samples ◽  
Endothelial Proliferation ◽  
Human Pulmonary Artery

Pulmonary arterial hypertension (PAH) is a fatal cardiopulmonary disease characterized by increased vascular cell proliferation with resistance to apoptosis and occlusive remodeling of the small pulmonary arteries in humans. The Notch family of proteins are proximal signaling mediators of an evolutionarily conserved pathway that effect cell proliferation, fate determination, and development. In endothelial cells (ECs), Notch receptor 2 (Notch2) has been shown to promote endothelial apoptosis. However, a pro- or anti-proliferative role for Notch2 in pulmonary endothelial proliferation and ensuing PAH is unknown. Herein, we postulated that suppressed Notch2 signaling drives pulmonary endothelial proliferation in the setting of PAH. We observed that levels of Notch2 are ablated in lung and PA tissue samples from PAH patients compared to non-PAH controls. Interestingly, Notch2 expression was attenuated in human pulmonary artery endothelial cells (hPAECs) exposed to vasoactive factors including hypoxia, TGFβ, ET-1, and IGF-1. Gene silencing of Notch2 increased EC proliferation and reduced apoptosis. At the molecular level, Notch2-deficient hPAECs activated Akt, Erk1/2 and anti-apoptotic protein Bcl-2, and reduced levels of p21cip and Bax. Intriguingly, loss of Notch2 elicits a paradoxical activation of Notch1 and transcriptional upregulation of canonical Notch target genes Hes1, Hey1 and Hey2. Further, reduction in Rb and increased E2F1 binding to the Notch1 promoter appear to explain the upregulation of Notch1. In aggregate, our results demonstrate that loss of Notch2 derepresses Notch1 and elicits aberrant EC hallmarks of PAH. The data underscore a novel role for Notch in the maintenance of endothelial cell homeostasis.

scholarly journals Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study

Rheumatology ◽  
2020 ◽  
Vol 60 (1) ◽  
pp. 399-407 ◽  
Author(s):  
Jose Luis Rodriguez-Garcia ◽  
Gines Sanchez-Nievas ◽  
Juan Arevalo-Serrano ◽  
Cristina Garcia-Gomez ◽  
Jose Maria Jimenez-Vizuete ◽  
...  
Keyword(s):  
Pulmonary Function ◽  
Viral Entry ◽  
Supplemental Oxygen ◽  
Janus Kinase ◽  
Arterial Oxygen ◽  
High Dose ◽  
Observational Cohort ◽  
Fraction Of Inspired Oxygen ◽  
Mean Differences ◽  
Inspired Oxygen

Abstract Objectives The Janus kinase (JAK) inhibitor baricitinib may block viral entry into pneumocytes and prevent cytokine storm in patients with SARS-CoV-2 pneumonia. We aimed to assess whether baricitinib improved pulmonary function in patients treated with high-dose corticosteroids for moderate to severe SARS-CoV-2 pneumonia. Methods This observational study enrolled patients with moderate to severe SARS-CoV-2 pneumonia [arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) &lt;200 mmHg] who received lopinavir/ritonavir and HCQ plus either corticosteroids (CS group, n = 50) or corticosteroids and baricitinib (BCT-CS group, n = 62). The primary end point was the change in oxygen saturation as measured by pulse oximetry (SpO2)/FiO2 from hospitalization to discharge. Secondary end points included the proportion of patients requiring supplemental oxygen at discharge and 1 month later. Statistics were adjusted by the inverse propensity score weighting (IPSW). Results A greater improvement in SpO2/FiO2 from hospitalization to discharge was observed in the BCT-CS vs CS group (mean differences adjusted for IPSW, 49; 95% CI: 22, 77; P &lt; 0.001). A higher proportion of patients required supplemental oxygen both at discharge (62.0% vs 25.8%; reduction of the risk by 82%, OR adjusted for IPSW, 0.18; 95% CI: 0.08, 0.43; P &lt; 0.001) and 1 month later (28.0% vs 12.9%, reduction of the risk by 69%, OR adjusted for IPSW, 0.31; 95% CI: 0.11, 0.86; P = 0.024) in the CS vs BCT-CS group. Conclusions . In patients with moderate to severe SARS-CoV-2 pneumonia a combination of baricitinib with corticosteroids was associated with greater improvement in pulmonary function when compared with corticosteroids alone. Trial registration European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, ENCEPP (EUPAS34966, http://www.encepp.eu/encepp/viewResource.htm? id = 34967)

scholarly journals MLC901 Favors Angiogenesis and Associated Recovery after Ischemic Stroke in Mice

2016 ◽  
Vol 42 (1-2) ◽  
pp. 139-154 ◽  
Author(s):  
Carine Gandin ◽  
Catherine Widmann ◽  
Michel Lazdunski ◽  
Catherine Heurteaux
Keyword(s):  
Ischemic Stroke ◽  
Neurovascular Unit ◽  
Artery Occlusion ◽  
Herbal Extract ◽  
Endothelial Cell Proliferation ◽  
Vascular Endothelial ◽  
Preventive Action ◽  
Important Player ◽  
Endothelial Growth Factor ◽  
Cerebral Artery Occlusion

Background: There is increasing evidence that angiogenesis, through new blood vessel formation, results in improved collateral circulation and may impact the long-term recovery of patients. In this study, we first investigated the preventive action of a 5-week pretreatment of MLC901, an herbal extract preparation derived from Chinese medicine, against the deleterious effects of ischemic stroke and its effects on angiogenesis in a model of focal ischemia in mice. Methods: The stroke model was induced by 60 min of middle cerebral artery occlusion followed by reperfusion. MLC901 was administered in the drinking water of animals (6 g/l) for 5 weeks before ischemia and then during reperfusion. Results: MLC901 treatment increased the survival rate, reduced the cerebral infarct area and attenuated the blood brain barrier leakage as well as the neurologic dysfunction following ischemia and reperfusion. We provide evidence that MLC901 enhances endothelial cell proliferation and angiogenesis by increasing the number of neocortical vessels in the infarcted area. MLC901 regulates the expression of hypoxic inducible factor 1α and its downstream targets such as vascular endothelial growth factor and angiopoietins 1 and 2. This work also shows that erythropoietin is an important player in the enhancement of angiogenesis by MLC901. Conclusions: These results demonstrate therapeutic properties of MLC901, in addition to those previously described, in stimulating revascularization, neuroprotection and repair of the neurovascular unit after ischemic stroke.

scholarly journals Regulation of thrombospondin-1 by natural and synthetic progestins in human breast cancer cells

2009 ◽  
Vol 16 (3) ◽  
pp. 809-817 ◽  
Author(s):  
Salman M Hyder ◽  
Yayun Liang ◽  
Jianbo Wu ◽  
Vanessa Welbern
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
P53 Protein ◽  
Endothelial Cell Proliferation ◽  
Ru 486 ◽  
Thrombospondin 1 ◽  
Treated Breast ◽  
Endothelial Growth Factor ◽  
Natural And Synthetic

Our recent studies show that progestins induce vascular endothelial growth factor (VEGF) in breast cancer cells that express mutant p53 protein. Here, we show that natural and synthetic progestins also induce thrombospondin-1 (TSP-1) mRNA and protein in T47-D and BT-474 breast cancer cells. Antiprogestin RU-486 inhibits the induction of VEGF and TSP-1 by progestins, suggesting that this effect of progestin is mediated by the progesterone receptor (PR). Actinomycin-D, but not puromycin, also blocks progestin-dependent induction of TSP-1. A putative progestin-response element was identified in the human TSP-1 promoter, which is consistent with the hypothesis that a progestin–PR complex might directly regulate transcription of the TSP-1 gene in human cells. Conditioned medium from progestin-treated breast cancer cells stimulates endothelial cell proliferation in the absence though not in the presence of antibody to TSP-1, indicating that TSP-1 secreted by breast cancer cells could be pro-angiogenic. Since tumor cell-derived TSP-1 has the potential to promote angiogenesis in the tumor microenvironment, it could be a potential target for breast cancer therapy.

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