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Mechanisms of VEGF (Vascular Endothelial Growth Factor) Inhibitor-Associated Hypertension and Vascular Disease.
Pandey AK, Singhi EK, Arroyo JP, Ikizler TA, Gould ER, Brown J, Beckman JA, Harrison DG, Moslehi J
(2018) Hypertension 71: e1-e8
MeSH Terms: Angiogenesis Inhibitors, Animals, Humans, Hypertension, Signal Transduction, Vascular Diseases, Vascular Endothelial Growth Factor A
Added April 22, 2018
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7 MeSH Terms
Cardio-Oncology: Vascular Endothelial Growth Factor Inhibitors, Salt, and Macrophages: A Complicated Interaction.
Moslehi J, Pandey AK, Bhatia N
(2017) Hypertension 69: 785-786
MeSH Terms: Humans, Macrophages, Sodium Chloride, Sodium Chloride, Dietary, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factors
Added March 26, 2017
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6 MeSH Terms
Skeletal Colonization by Breast Cancer Cells Is Stimulated by an Osteoblast and β2AR-Dependent Neo-Angiogenic Switch.
Mulcrone PL, Campbell JP, Clément-Demange L, Anbinder AL, Merkel AR, Brekken RA, Sterling JA, Elefteriou F
(2017) J Bone Miner Res 32: 1442-1454
MeSH Terms: Animals, Bone and Bones, Breast Neoplasms, Cell Line, Tumor, Coculture Techniques, Female, Humans, Mice, Mice, Knockout, Neoplasm Metastasis, Neoplasm Proteins, Neovascularization, Pathologic, Osteoblasts, Receptors, Adrenergic, beta-2, Vascular Endothelial Growth Factor A
Show Abstract · Added April 26, 2017
The skeleton is a common site for breast cancer metastasis. Although significant progress has been made to manage osteolytic bone lesions, the mechanisms driving the early steps of the bone metastatic process are still not sufficiently understood to design efficacious strategies needed to inhibit this process and offer preventative therapeutic options. Progression and recurrence of breast cancer, as well as reduced survival of patients with breast cancer, are associated with chronic stress, a condition known to stimulate sympathetic nerve outflow. In this study, we show that stimulation of the beta 2-adrenergic receptor (β2AR) by isoproterenol, used as a pharmacological surrogate of sympathetic nerve activation, led to increased blood vessel density and Vegf-a expression in bone. It also raised levels of secreted Vegf-a in osteoblast cultures, and accordingly, the conditioned media from isoproterenol-treated osteoblast cultures promoted new vessel formation in two ex vivo models of angiogenesis. Blocking the interaction between Vegf-a and its receptor, Vegfr2, blunted the increase in vessel density induced by isoproterenol. Genetic loss of the β2AR globally, or specifically in type 1 collagen-expressing osteoblasts, diminished the increase in Vegf-positive osteoblast number and bone vessel density induced by isoproterenol, and reduced the higher incidence of bone metastatic lesions induced by isoproterenol after intracardiac injection of an osteotropic variant of MDA-MB-231 breast cancer cells. Inhibition of the interaction between Vegf-a and Vegfr2 with the blocking antibody mcr84 also prevented the increase in bone vascular density and bone metastasis triggered by isoproterenol. Together, these results indicate that stimulation of the β2AR in osteoblasts triggers a Vegf-dependent neo-angiogenic switch that promotes bone vascular density and the colonization of the bone microenvironment by metastatic breast cancer cells. © 2017 American Society for Bone and Mineral Research.
© 2017 American Society for Bone and Mineral Research.
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Associations between Tumor Vascularity, Vascular Endothelial Growth Factor Expression and PET/MRI Radiomic Signatures in Primary Clear-Cell-Renal-Cell-Carcinoma: Proof-of-Concept Study.
Yin Q, Hung SC, Wang L, Lin W, Fielding JR, Rathmell WK, Khandani AH, Woods ME, Milowsky MI, Brooks SA, Wallen EM, Shen D
(2017) Sci Rep 7: 43356
MeSH Terms: Adult, Aged, Carcinoma, Renal Cell, Female, Gene Expression, Humans, Image Interpretation, Computer-Assisted, Kidney Neoplasms, Magnetic Resonance Imaging, Male, Middle Aged, Neovascularization, Pathologic, Positron-Emission Tomography, Proof of Concept Study, Retrospective Studies, Tumor Burden, Vascular Endothelial Growth Factor A
Show Abstract · Added October 30, 2019
Studies have shown that tumor angiogenesis is an essential process for tumor growth, proliferation and metastasis. Also, tumor angiogenesis is an important prognostic factor of clear cell renal cell carcinoma (ccRCC), as well as a factor in guiding treatment with antiangiogenic agents. Here, we attempted to find the associations between tumor angiogenesis and radiomic imaging features from PET/MRI. Specifically, sparse canonical correlation analysis was conducted on 3 feature datasets (i.e., radiomic imaging features, tumor microvascular density (MVD), and vascular endothelial growth factor (VEGF) expression) from 9 patients with primary ccRCC. In order to overcome the potential bias of intratumoral heterogeneity of angiogenesis, this study investigated the relationship between regional expressions of angiogenesis and VEGF, and localized radiomic features from different parts within the tumors. Our study highlighted the significant strong correlations between radiomic features and MVD, and also demonstrated that the spatiotemporal features extracted from DCE-MRI provided stronger radiomic correlation to MVD than the textural features extracted from Dixon sequences and FDG PET. Furthermore, PET/MRI, which takes advantage of the combined functional and structural information, had higher radiomics correlation to MVD than solely utilizing PET or MRI alone.
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Novel Small Molecule JP-153 Targets the Src-FAK-Paxillin Signaling Complex to Inhibit VEGF-Induced Retinal Angiogenesis.
Toutounchian JJ, Pagadala J, Miller DD, Baudry J, Park F, Chaum E, Morales-Tirado , Yates CR
(2017) Mol Pharmacol 91: 1-13
MeSH Terms: Animals, Benzoxazines, Cell Movement, Cell Proliferation, Disease Models, Animal, Endothelial Cells, Focal Adhesion Protein-Tyrosine Kinases, Humans, Mice, Inbred C57BL, Models, Biological, Oxygen, Paxillin, Retinal Neovascularization, Signal Transduction, Small Molecule Libraries, Vascular Endothelial Growth Factor A, src-Family Kinases
Show Abstract · Added June 11, 2018
Targeting vascular endothelial growth factor (VEGF) is a common treatment strategy for neovascular eye disease, a major cause of vision loss in diabetic retinopathy and age-related macular degeneration. However, the decline in clinical efficacy over time in many patients suggests that monotherapy of anti-VEGF protein therapeutics may benefit from adjunctive treatments. Our previous work has shown that through decreased activation of the cytoskeletal protein paxillin, growth factor-induced ischemic retinopathy in the murine oxygen-induced retinopathy model could be inhibited. In this study, we demonstrated that VEGF-dependent activation of the Src/FAK/paxillin signalsome is required for human retinal endothelial cell migration and proliferation. Specifically, the disruption of focal adhesion kinase (FAK) and paxillin interactions using the small molecule JP-153 inhibited Src-dependent phosphorylation of paxillin (Y118) and downstream activation of Akt (S473), resulting in reduced migration and proliferation of retinal endothelial cells stimulated with VEGF. However, this effect did not prevent the initial activation of either Src or FAK. Furthermore, topical application of a JP-153-loaded microemulsion affected the hallmark features of pathologic retinal angiogenesis, reducing neovascular tuft formation and increased avascular area, in a dose-dependent manner. In conclusion, our results suggest that using small molecules to modulate the focal adhesion protein paxillin is an effective strategy for treating pathologic retinal neovascularization. To our knowledge, this is the first paradigm validating modulation of paxillin to inhibit angiogenesis. As such, we have identified and developed a novel class of small molecules aimed at targeting focal adhesion protein interactions that are essential for pathologic neovascularization in the eye.
Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.
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Plasma hepatocyte growth factor is a novel marker of AL cardiac amyloidosis.
Swiger KJ, Friedman EA, Brittain EL, Tomasek KA, Huang S, Su YR, Sawyer DB, Lenihan DJ
(2016) Amyloid 23: 242-248
MeSH Terms: Aged, Amyloidosis, Biomarkers, Cardiomyopathies, Cohort Studies, Diagnosis, Differential, Female, Galectin 3, Heart Failure, Systolic, Hepatocyte Growth Factor, Humans, Hypertrophy, Left Ventricular, Immunoglobulin Light Chains, Interleukin-6, Male, Middle Aged, Prealbumin, Registries, Survival Analysis, Vascular Endothelial Growth Factor A
Show Abstract · Added June 7, 2018
BACKGROUND - Cardiac amyloidosis is an infiltrative cardiomyopathy that is challenging to diagnose. We hypothesized that the novel biomarkers hepatocyte growth factor (HGF), galectin-3 (GAL-3), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF) would be elevated in cardiac amyloidosis and may be able to discriminate from non-cardiac systemic amyloidosis or other cardiomyopathies with similar clinical or morphologic characteristics.
METHODS - Patients were selected from the Vanderbilt Main Heart Registry according to the following groups: (1) amyloid light-chain (AL) cardiac amyloidosis (n = 26); (2) transthyretin (ATTR) cardiac amyloidosis (n = 7); (3) left ventricular hypertrophy (LVH) (n = 45); (4) systolic heart failure (n = 42); and (5) non-cardiac systemic amyloidosis (n = 7). Biomarkers were measured in stored plasma samples. Biomarkers' discrimination performance in predicting AL cardiac amyloidosis (i.e., Concordance index) was reported. A survival analysis was used to explore the relationship between HGF levels and mortality among AL cardiac amyloidosis patients.
RESULTS - HGF levels were markedly elevated in patients with AL cardiac amyloidosis (median = 622, interquartile range (IQR): 299-1228 pg/mL) compared with the other groups, including those with non-cardiac systemic amyloidosis (median = 134, IQR: 94-163 pg/mL, p < 0.001). HGF was not a specific marker for ATTR amyloidosis. Gal-3 was elevated in all groups with amyloidosis but could not differentiate between those with and without cardiac involvement. There was no difference in IL-6 or VEGF between those with AL cardiac amyloidosis compared to other groups (p = 0.13 and 0.057, respectively).
CONCLUSIONS - HGF may be a specific marker that distinguishes AL cardiac amyloidosis from other cardiomyopathies with similar clinical or morphologic characteristics. Further studies are necessary to determine whether HGF levels predict the likelihood of survival.
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Cardiovascular Toxic Effects of Targeted Cancer Therapies.
Moslehi JJ
(2016) N Engl J Med 375: 1457-1467
MeSH Terms: Antineoplastic Agents, Cardiovascular Diseases, Humans, Neoplasms, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Signal Transduction, Vascular Endothelial Growth Factor A
Added March 26, 2017
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Interstitial renal fibrosis due to multiple cisplatin treatments is ameliorated by semicarbazide-sensitive amine oxidase inhibition.
Katagiri D, Hamasaki Y, Doi K, Negishi K, Sugaya T, Nangaku M, Noiri E
(2016) Kidney Int 89: 374-85
MeSH Terms: Actins, Acute Kidney Injury, Allylamine, Amine Oxidase (Copper-Containing), Animals, Antineoplastic Agents, Benzamides, Chemokine CCL2, Cisplatin, Drug Evaluation, Preclinical, Fatty Acid-Binding Proteins, Fibrosis, Interleukin-6, Kidney, Male, Mice, Inbred C57BL, Mice, Transgenic, Transforming Growth Factor beta, Tumor Necrosis Factor-alpha, Vascular Endothelial Growth Factor A
Show Abstract · Added February 11, 2016
Elucidation of acute kidney diseases and disorders (AKD), including acute kidney injury (AKI), is important to prevent their progression to chronic kidney disease. Current animal AKI models are often too severe for use in evaluating human AKI. Therefore, new animal models of mild kidney injury are needed. Here a new clinically relevant animal model using multiple low doses of cisplatin (CP) was used to evaluate AKD. When 10 mg/kg CP was administered intraperitoneally once weekly for three times to L-type fatty acid-binding protein (L-FABP) transgenic mice, moderate renal interstitial fibrosis and tubule dilatation occurred, accompanied by brush-border loss. Urinary L-FABP, a promising biomarker of AKI, changed more drastically than blood urea nitrogen or creatinine. Preventing fibrosis in organs was also studied. Oral administration of a recently reported selective semicarbazide-sensitive amine oxidase inhibitor, PXS-4728A, for 1 week attenuated kidney injury and interstitial fibrosis compared with vehicle. Inhibition of renal lipid accumulation in semicarbazide-sensitive amine oxidase inhibitor-treated mice, together with reduced oxidative stress and L-FABP suppression in proximal tubules, suggested an antifibrotic effect of semicarbazide-sensitive amine oxidase inhibition in this CP-AKD model, a representative onco-nephrology. Thus, semicarbazide-sensitive amine oxidase inhibitors may be promising candidates for the prevention of chronic kidney disease in patients using CP to treat malignancy.
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The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease.
Hohman TJ, Bell SP, Jefferson AL, Alzheimer’s Disease Neuroimaging Initiative
(2015) JAMA Neurol 72: 520-9
MeSH Terms: Aged, Aged, 80 and over, Aging, Alzheimer Disease, Amyloid beta-Peptides, Atrophy, Biomarkers, Cognitive Dysfunction, Cross-Sectional Studies, Executive Function, Female, Hippocampus, Humans, Longitudinal Studies, Male, Memory, Episodic, Peptide Fragments, Vascular Endothelial Growth Factor A, tau Proteins
Show Abstract · Added February 22, 2016
IMPORTANCE - A subset of older adults present post mortem with Alzheimer disease (AD) pathologic features but without any significant clinical manifestation of dementia. Vascular endothelial growth factor (VEGF) has been implicated in staving off AD-related neurodegeneration.
OBJECTIVE - To evaluate whether VEGF levels are associated with brain aging outcomes (hippocampal volume and cognition) and to further evaluate whether VEGF modifies relations between AD biomarkers and brain aging outcomes.
DESIGN, SETTING, AND PARTICIPANTS - Biomarker analysis using neuroimaging and neuropsychological outcomes from the Alzheimer's Disease Neuroimaging Initiative. This prospective longitudinal study across North America included individuals with normal cognition (n = 90), mild cognitive impairment (n = 130), and AD (n = 59) and began in October 2004, with follow-up ongoing.
MAIN OUTCOMES AND MEASURES - Cerebrospinal fluid VEGF was cross-sectionally related to brain aging outcomes (hippocampal volume, episodic memory, and executive function) using a general linear model and longitudinally using mixed-effects regression. Alzheimer disease biomarker (cerebrospinal fluid β-amyloid 42 and total tau)-by-VEGF interactions evaluated the effect of VEGF on brain aging outcomes in the presence of enhanced AD biomarkers.
RESULTS - Vascular endothelial growth factor was associated with baseline hippocampal volume (t277 = 2.62; P = .009), longitudinal hippocampal atrophy (t858 = 2.48; P = .01), and longitudinal decline in memory (t1629 = 4.09; P < .001) and executive function (t1616 = 3.00; P = .003). Vascular endothelial growth factor interacted with tau in predicting longitudinal hippocampal atrophy (t845 = 4.17; P < .001), memory decline (t1610 = 2.49; P = .01), and executive function decline (t1597 = 3.71; P < .001). Vascular endothelial growth factor interacted with β-amyloid 42 in predicting longitudinal memory decline (t1618 = -2.53; P = .01).
CONCLUSIONS AND RELEVANCE - Elevated cerebrospinal fluid VEGF was associated with more optimal brain aging in vivo. The neuroprotective effect appeared strongest in the presence of enhanced AD biomarkers, suggesting that VEGF may be particularly beneficial in individuals showing early hallmarks of the AD cascade. Future work should evaluate the interaction between VEGF expression in vitro and pathologic burden to address potential mechanisms.
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Regulation of endothelial cell proliferation and vascular assembly through distinct mTORC2 signaling pathways.
Wang S, Amato KR, Song W, Youngblood V, Lee K, Boothby M, Brantley-Sieders DM, Chen J
(2015) Mol Cell Biol 35: 1299-313
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Carrier Proteins, Cell Proliferation, Cells, Cultured, Endothelial Cells, Gene Deletion, Human Umbilical Vein Endothelial Cells, Humans, Mechanistic Target of Rapamycin Complex 2, Mice, Multiprotein Complexes, Neovascularization, Physiologic, Phosphorylation, Protein Kinase C-alpha, Proto-Oncogene Proteins c-akt, Rapamycin-Insensitive Companion of mTOR Protein, Regulatory-Associated Protein of mTOR, Signal Transduction, TOR Serine-Threonine Kinases, Vascular Endothelial Growth Factor A
Show Abstract · Added February 15, 2016
Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates a diverse array of cellular processes, including cell growth, survival, metabolism, and cytoskeleton dynamics. mTOR functions in two distinct complexes, mTORC1 and mTORC2, whose activities and substrate specificities are regulated by complex specific cofactors, including Raptor and Rictor, respectively. Little is known regarding the relative contribution of mTORC1 versus mTORC2 in vascular endothelial cells. Using mouse models of Raptor or Rictor gene targeting, we discovered that Rictor ablation inhibited vascular endothelial growth factor (VEGF)-induced endothelial cell proliferation and assembly in vitro and angiogenesis in vivo, whereas the loss of Raptor had only a modest effect on endothelial cells (ECs). Mechanistically, the loss of Rictor reduced the phosphorylation of AKT, protein kinase Cα (PKCα), and NDRG1 without affecting the mTORC1 pathway. In contrast, the loss of Raptor increased the phosphorylation of AKT despite inhibiting the phosphorylation of S6K1, a direct target of mTORC1. Reconstitution of Rictor-null cells with myristoylated AKT (Myr-AKT) rescued vascular assembly in Rictor-deficient endothelial cells, whereas PKCα rescued proliferation defects. Furthermore, tumor neovascularization in vivo was significantly decreased upon EC-specific Rictor deletion in mice. These data indicate that mTORC2 is a critical signaling node required for VEGF-mediated angiogenesis through the regulation of AKT and PKCα in vascular endothelial cells.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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