scholarly journals Rare variants in previously identified linkage regions associated with carotid plaque in Dominican Republic families

PLoS ONE ◽  
2022 ◽  
Vol 17 (1) ◽  
pp. e0250799
Author(s):  
Nicole D. Dueker ◽  
Ashley Beecham ◽  
Liyong Wang ◽  
Chuanhui Dong ◽  
Ralph L. Sacco ◽  
...  
Keyword(s):  
Carotid Plaque ◽  
Rare Variants ◽  
Missense Variant ◽  
Targeted Sequencing ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Chromosome 11 ◽  
Familial Data ◽  
The One ◽  
Endothelial Growth Factor

Carotid plaque is a subclinical measure of atherosclerosis. We have previously shown measures of carotid plaque to be heritable in a sample of 100 Dominican families and found evidence for linkage and association of common variants (CVs) on 7q36, 11p15, 14q32 and 15q23 with plaque presence. Our current study aimed to refine these regions further and identify rare variants (RVs) influencing plaque presence. Therefore, we performed targeted sequencing of the one LOD unit down region on 7q36, 11p15, 14q32 and 15q23 in 12 Dominican families with evidence for linkage to plaque presence. Gene-based RV analyses were performed using the Sequence Association Test for familial data (F-SKAT) under two filtering algorithms; 1. all exonic RVs and 2. non-synonymous RVs. Replication analyses were performed using a sample of 22 Dominican families and 556 unrelated Dominicans with Exome Array data. To identify additional non-synonymous RVs influencing plaque, we looked for co-segregation of RVs with plaque in each of the sequenced families. Our most strongly associated gene with evidence for replication was AMPD3 which showed suggestive association with plaque presence in the sequenced families (exonic RV p = 0.003, nonsynonymous RV p = 0.005) and replication families (exonic RV p = 0.04, nonsynonymous RV p = 0.02). Examination of the sequenced family pedigrees revealed two missense variants on chromosome 11 which co-segregated with plaque presence in one of our families; rs61751342 (located in DENND2B), and rs61760882 (located in RNF141). The rs61751342 missense variant is an eQTL for SCUBE2 in the atrial appendage. Notably, SCUBE2 encodes a protein which interacts with vascular endothelial growth factor (VEGF) receptor 2 to regulate VEGF-induced angiogenesis, thus providing biologic plausibility for this gene in atherosclerosis. In conclusion, using targeted sequencing of previously-identified linkage regions, we have identified suggestive evidence for the role of RVs in carotid plaque pathogenesis.

Expression Profile of VEGF-C, VEGF-D, and VEGFR-3 in Different Grades of Endometrial Cancer

2019 ◽  
Vol 20 (12) ◽  
pp. 1004-1010
Author(s):  
Marcin Oplawski ◽  
Konrad Dziobek ◽  
Nikola Zmarzły ◽  
Beniamin Grabarek ◽  
Tomasz Halski ◽  
...  
Keyword(s):  
Endometrial Cancer ◽  
Optical Density ◽  
Metastatic Potential ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Tumor Lymphangiogenesis ◽  
Neoplastic Process ◽  
The One ◽  
Post Hoc ◽  
Endothelial Growth Factor

Background: Vascular endothelial growth factor (VEGF)-C, -D, and VEGF receptor-3 are proteins characterized as crucial for tumor lymphangiogenesis. It is accompanied by angiogenesis during wound healing, but also in the neoplastic process. The research studies have shown that the lymphatic system plays a key role in the progression of carcinogenesis. Objective: The aim of this study was to evaluate changes in the expression of VEGF-C, VEGF-D and VEGFR-3 in different grades of endometrial cancer (G1-G3). Methods: The study included 45 patients diagnosed with endometrial cancer (G1=17; G2=15; G3=13) and 15 patients without neoplastic changes. The expression of VEGF-C, VEGF-D, and VEGFR-3 was assessed using microarray technique and immunohistochemistry. Statistical analysis was performed using the one-way ANOVA and Tukey's post-hoc test. Results: Statistically significant changes in the expression at the transcriptome level were found only in the case of VEGF-C (G1 vs. C, fold change - FC = -1.15; G2 vs. C, FC = -2.33; G3 vs. C, FC = - 1.68). However, VEGF-D and VEGFR-3 were expressed at the protein level. Analysis of VEGF-D expression showed that the optical density of the reaction product in G1 reached 101.7, while the values in G2 and G3 were 142.7 and 184.4, respectively. For VEGF-R3, the optical density of the reaction product reached the following levels: 72 in control, 118.77 in G1, 145.8 in G2, and 170.9 in G3. Conclusion: : An increase in VEGF-D and VEGFR-3 levels may indicate that VEGF-D-dependent processes are intensified along with the dedifferentiation of tumor cells. The lack of VEGF-C expression in endometrial cancer samples may suggest that this tumor is characterized by a different mechanism of metastasis than EMT. Our study emphasizes that when analyzing the metastatic potential of cancer, the expression of more than one factor should be taken into account.

scholarly journals Lipid Raft Association Stabilizes VEGF Receptor 2 in Endothelial Cells

2021 ◽  
Vol 22 (2) ◽  
pp. 798
Author(s):  
Ibukunoluwapo O. Zabroski ◽  
Matthew A. Nugent
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Endothelial Cells ◽  
Lipid Rafts ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Potential Mechanism ◽  
Lysosomal Degradation ◽  
Extracellular Signal ◽  
The Stability ◽  
Endothelial Growth Factor

The binding of vascular endothelial growth factor A (VEGF) to VEGF receptor-2 (VEGFR-2) stimulates angiogenic signaling. Lipid rafts are cholesterol-dense regions of the plasma membrane that serve as an organizational platform for biomolecules. Although VEGFR2 has been shown to colocalize with lipid rafts to regulate its activation, the effect of lipid rafts on non-activated VEGFR2 has not been explored. Here, we characterized the involvement of lipid rafts in modulating the stability of non-activated VEGFR2 in endothelial cells using raft disrupting agents: methyl-β-cyclodextrin, sphingomyelinase and simvastatin. Disrupting lipid rafts selectively decreased the levels of non-activated VEGFR2 as a result of increased lysosomal degradation. The decreased expression of VEGFR2 translated to reduced VEGF-activation of the extracellular signal-regulated protein kinases (ERK). Overall, our results indicate that lipid rafts stabilize VEGFR2 and its associated signal transduction activities required for angiogenesis. Thus, modulation of lipid rafts may provide a means to regulate the sensitivity of endothelial cells to VEGF stimulation. Indeed, the ability of simvastatin to down regulate VEGFR2 and inhibit VEGF activity suggest a potential mechanism underlying the observation that this drug improves outcomes in the treatment of certain cancers.

scholarly journals Perforation of the Small Intestine after Introduction of Lenvatinib in a Patient with Advanced Hepatocellular Carcinoma

2020 ◽  
Vol 14 (1) ◽  
pp. 63-69 ◽  
Author(s):  
Naomi Suzuki ◽  
Kazuto Tajiri ◽  
Yuka Futsukaichi ◽  
Shinichi Tanaka ◽  
Aiko Murayama ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Small Intestine ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Vegf Receptor ◽  
Advanced Hepatocellular Carcinoma ◽  
Vascular Endothelial ◽  
First Line ◽  
Endothelial Growth Factor ◽  
Line Standard

Lenvatinib is a first-line standard treatment for advanced hepatocellular carcinoma (HCC) with better anti-tumor effects than sorafenib, as shown by greater inhibition of the kinases of fibroblast growth factor receptor and vascular endothelial growth factor (VEGF) receptor. This report describes a patient with advanced HCC who experienced perforation of the small intestine 1 month after starting the treatment with lenvatinib. This patient likely had partial necrosis of a metastasis to the small intestine before starting lenvatinib treatment, with subsequent ischemic changes leading to perforation of the small intestine. Although metastasis of HCC to the small intestine is rare, patients with these metastases should be regarded as being at risk for perforation during lenvatinib treatment.

Vascular endothelial growth factor-C stimulates the lymphatic pump by a VEGF receptor-3-dependent mechanism

2007 ◽  
Vol 293 (1) ◽  
pp. H709-H718 ◽  
Author(s):  
Jerome W. Breslin ◽  
Nathalie Gaudreault ◽  
Katherine D. Watson ◽  
Rashell Reynoso ◽  
Sarah Y. Yuan ◽  
...  
Keyword(s):  
Stroke Volume ◽  
Stroke Volume Index ◽  
Volume Index ◽  
Flow Index ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Contraction Frequency ◽  
Pump Activity ◽  
Endothelial Growth Factor ◽  
Arteriolar Diameter

Vascular endothelial growth factor (VEGF)-C plays an important role in lymphangiogenesis; however, functional responses of lymphatic vessels to VEGF-C have not been characterized. We tested the hypothesis that VEGF-C-induced activation of VEGF receptor (VEGFR)-3 increases lymphatic pump output. We examined the in vivo pump activity of rat mesenteric collecting lymphatics using intravital microscopy during basal conditions and during treatment with 1 nM recombinant VEGF-C, the selective VEGFR-3 agonist VEGF-Cys156Ser mutation (C156S; 1 nM), or 0.1 nM VEGF-A. Their specific responses were also analyzed during selective inhibition of VEGFR-3 with MAZ-51. Contraction frequency, end-diastolic diameter, end-systolic diameter, stroke volume index, pump flow index, and ejection fraction were evaluated. We also assessed arteriolar diameter and microvascular extravasation of FITC-albumin. The results show that both VEGF-C and VEGF-C156S significantly increased contraction frequency, end-diastolic diameter, stroke volume index, and pump flow index in a time-dependent manner. VEGF-A caused a different response characterized by a significantly increased stroke volume after 30 min of treatment. MAZ-51 (5 μM) caused tonic constriction and decreased contraction frequency. In addition, 0.5 and 5 μM MAZ-51 attenuated VEGF-C- and VEGF-C156S-induced lymphatic pump activation. VEGF-A caused vasodilation of arterioles, whereas VEGF-C and VEGF-C156S did not significantly alter arteriolar diameter. Also, VEGF-A and VEGF-C caused increased microvascular permeability, whereas VEGF-C156S did not. Our results demonstrate that VEGF-C increases lymphatic pumping through VEGFR-3. Furthermore, changes in microvascular hemodynamics are not required for VEGFR-3-mediated changes in lymphatic pump activity.

scholarly journals Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot

2021 ◽  
Author(s):  
Doris Škorić-Milosavljević ◽  
Najim Lahrouchi ◽  
Fernanda M. Bosada ◽  
Gregor Dombrowsky ◽  
Simon G. Williams ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Tetralogy Of Fallot ◽  
Large Scale ◽  
Rare Variants ◽  
Growth Factor Receptor ◽  
Vegf Receptor ◽  
Loss Of Function ◽  
Endothelial Growth Factor

Abstract Purpose Rare genetic variants in KDR, encoding the vascular endothelial growth factor receptor 2 (VEGFR2), have been reported in patients with tetralogy of Fallot (TOF). However, their role in disease causality and pathogenesis remains unclear. Methods We conducted exome sequencing in a familial case of TOF and large-scale genetic studies, including burden testing, in >1,500 patients with TOF. We studied gene-targeted mice and conducted cell-based assays to explore the role of KDR genetic variation in the etiology of TOF. Results Exome sequencing in a family with two siblings affected by TOF revealed biallelic missense variants in KDR. Studies in knock-in mice and in HEK 293T cells identified embryonic lethality for one variant when occurring in the homozygous state, and a significantly reduced VEGFR2 phosphorylation for both variants. Rare variant burden analysis conducted in a set of 1,569 patients of European descent with TOF identified a 46-fold enrichment of protein-truncating variants (PTVs) in TOF cases compared to controls (P = 7 × 10-11). Conclusion Rare KDR variants, in particular PTVs, strongly associate with TOF, likely in the setting of different inheritance patterns. Supported by genetic and in vivo and in vitro functional analysis, we propose loss-of-function of VEGFR2 as one of the mechanisms involved in the pathogenesis of TOF.

Vasodilator effect and mechanism of action of vascular endothelial growth factor in skin vasculature

2004 ◽  
Vol 286 (3) ◽  
pp. H946-H954 ◽  
Author(s):  
Homa Ashrafpour ◽  
Ning Huang ◽  
Peter C. Neligan ◽  
Christopher R. Forrest ◽  
Patrick D. Addison ◽  
...  
Keyword(s):  
Skin Flap ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Skin Flaps ◽  
Skin Perfusion ◽  
Potent Vasodilator ◽  
Or Gene ◽  
Endothelial Growth Factor ◽  
Endothelial Nitric Oxide ◽  
First Time

Various laboratories have reported that local subcutaneous or subdermal injection of VEGF165 at the time of surgery effectively attenuated ischemic necrosis in rat skin flaps, but the mechanism was not studied and enhanced angiogenesis was implicated. In the present study, we used the clinically relevant isolated perfused 6 × 16-cm pig buttock skin flap model to 1) test our hypothesis that VEGF165 is a potent vasodilator and acute VEGF165 treatment increases skin perfusion; and 2) investigate the mechanism of VEGF165-induced skin vasorelaxation. We observed that VEGF165 (5 × 10–16–5 × 10–11 M) elicited a concentration-dependent decrease in perfusion pressure (i.e., vasorelaxation) in skin flaps preconstricted with a submaximal concentration of norepinephrine (NE), endothelin-1, or U-46619. The VEGF165-induced skin vasorelaxation was confirmed using a dermofluorometry technique for assessment of skin perfusion. The vasorelaxation potency of VEGF165 in NE-preconstricted skin flaps (pD2 = 13.57 ± 0.31) was higher ( P < 0.05) than that of acetylcholine (pD2 = 7.08 ± 0.24). Human placental factor, a specific VEGF receptor-1 agonist, did not elicit any vasorelaxation effect. However, a specific antibody to VEGF receptor-2 (1 μg/ml) or a specific VEGF receptor-2 inhibitor (5 × 10–6 M SU-1498) blocked the vasorelaxation effect of VEGF165 in NE-preconstricted skin flaps. These observations indicate that the potent vasorelaxation effect of VEGF165 in the skin vasculature is initiated by the activation of VEGF receptor-2. Furthermore, using pharmacological probes, we observed that the postreceptor signaling pathways of VEGF165-induced skin vasorelaxation involved activation of phospholipase C and protein kinase C, an increase in inositol 1,4,5-trisphosphate activity, release of the intra-cellular Ca2+ store, and synthesis/release of endothelial nitric oxide, which predominantly triggered the effector mechanism of VEGF165-induced vasorelaxation. This information provides, for the first time, an important insight into the mechanism of VEGF165 protein or gene therapy in the prevention/treatment of ischemia in skin flap surgery and skin ischemic diseases.

Vascular endothelial growth factor-induced secretion of fibronectin is ERK dependent

2004 ◽  
Vol 286 (3) ◽  
pp. L539-L545 ◽  
Author(s):  
Altaf S. Kazi ◽  
Shidan Lotfi ◽  
Elena A. Goncharova ◽  
Omar Tliba ◽  
Yassine Amrani ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Vascular Endothelial Growth Factor ◽  
Smooth Muscle ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Airway Remodeling ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Matrix Deposition ◽  
Endothelial Growth Factor

In severe asthma, cytokines and growth factors contribute to the proliferation of smooth muscle cells and blood vessels, and to the increased extracellular matrix deposition that constitutes the process of airway remodeling. Vascular endothelial growth factor (VEGF), which regulates vascular permeability and angiogenesis, also modulates the function of nonendothelial cell types. In this study, we demonstrate that VEGF induces fibronectin secretion by human airway smooth muscle (ASM) cells. In addition, stimulation of ASM with VEGF activates ERK, but not p38MAPK, and fibronectin secretion is ERK dependent. Both ERK activation and fibronectin secretion appear to be mediated through the VEGF receptor flt-1, as evidenced by the effects of the flt-1-specific ligand placenta growth factor. Finally, we demonstrate that ASM cells constitutively secrete VEGF, which is increased in response to PDGF, transforming growth factor-β, IL-1β, and PGE2. We conclude that ASM-derived VEGF, through modulation of the extracellular matrix, may play an important role in airway remodeling seen in asthma.

scholarly journals Vascular Endothelial Growth Factor Concentration in Brain of Rat Treated with Anaerobic Exercises

2015 ◽  
Vol 4 (3) ◽  
pp. 201
Author(s):  
Rostika Flora ◽  
Muhammad Zulkarnain ◽  
Yuliana Ardi ◽  
Esti Sorena ◽  
Roslina Wati ◽  
...  
Keyword(s):  
Wistar Rat ◽  
Anaerobic Exercise ◽  
Control Group ◽  
Vascular Endothelial ◽  
Exercise Frequency ◽  
Treatment Groups ◽  
The One ◽  
Short Time ◽  
Endothelial Growth Factor ◽  
Brain Tissues

Anaerobic  exercise is a high-intensity exercise that needs quick energy supplies obtained in a very short time. However, this exercise may result in tissue hypoxia which is characterized by the increase of HIF-1α concentration. The presence of HIF-1α will induce the secretion of VEGF and, eventually, trigger angiogenesis. Nevertheless, it is still unclear whether anaerobic exercise will also cause hypoxia in which this condition will increase the concentration of VEGF in brain tissues. The aim of this study was to find out the effect of anaerobic exercise frequency towards VEGF concentration of Wistar rat brain tissues.  Brain tissues were taken from rats treated with anaerobic exercise using treadmill. This exercise was given in different frequencies; one time, three times, and seven times a week.  The data collected were analyzed using independent t-test. The results of this study showed that anaerobic  exercise done once a week could significantly increase VEGF concentration (p &lt; 0.05) if compared with the one in control group (95.21 ± 31.99 v.s. 63.36 ± 11.01 pg/mL). Meanwhile, VEGF concentration of treatment groups given exercise three times a week (47.97 ± 10.68 pg/mL) and seven times a week (40.56 ± 13.98 pg/mL) showed a significant decrease if compared with that of control group (63.36 ± 11.01 pg/mL). Anaerobic  exercise affected VEGF concentration as an indicator of angiogenesis in brain tissue of wistar rats.

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