Modulation of VEGF receptor 2 signaling by protein phosphatases

Corti, Federico; Simons, Michael

doi:10.1016/j.phrs.2016.11.022

Cited by 45 publications

(44 citation statements)

References 266 publications

(353 reference statements)

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“…VEGFR2 is the main signal transducer for VEGF. The binding of VEGF results in receptor dimerization and autophosphorylation of the highly active receptor kinase region [47]. VEGFR2 was first identified as a major regulator of angiogenesis [48] and is now known to mediate endothelial cell proliferation, migration, permeability and survival [49][50][51].…”

Section: Introductionmentioning

confidence: 99%

VEGFR1 and VEGFR2 in Alzheimer’s Disease

Harris

Miners

Allen

et al. 2017

JAD

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Vascular endothelial growth factor (VEGF) is a potent angiogenic factor. Despite upregulation of VEGF in the brain in Alzheimer's disease (AD), probably in response to amyloid-␤, vasoconstriction, and tissue hypoxia, there is no consequent increase in microvessel density. VEGF binds to and activates VEGF receptor 2 (VEGFR2), but also binds to VEGF receptor 1 (VEGFR1), which exists in less-active membrane-bound and inactive soluble (sVEGFR1) forms and inhibits pro-angiogenic signaling. We have investigated whether altered expression of VEGF receptors might account for the lack of angiogenic response to VEGF in AD. We assessed the cellular distribution and protein level of VEGFR1 and VEGFR2 in parietal cortex from 50 AD and 36 age-matched control brains, and related the findings to measurements of VEGF and von Willebrand factor level (a marker of microvessel density) in the same tissue samples. VEGFR2 was expressed by neurons, astrocytes and endothelial cells. VEGFR1 was expressed predominantly neuronally and was significantly reduced in AD (p = 0.02). Western blot analysis on a subset of brains showed reduction in VEGFR1:sVEGFR1 in AD (p = 0.046). The lack of angiogenesis despite cerebral hypoperfusion in AD is not explained by altered expression of VEGFR2 or total VEGFR1; indeed, the downregulation of VEGFR1 may represent a pro-angiogenic response to the hypoperfusion. However, the relative increase in sVEGFR1 would be expected to have an anti-angiogenic effect which may be a factor in AD.

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Section: Introductionmentioning

confidence: 99%

VEGFR1 and VEGFR2 in Alzheimer’s Disease

Harris

Miners

Allen

et al. 2017

JAD

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“…VEGFR2-mediated activation of PI3K-AKT leads to eNOS phosphorylation, increased NO generation and consequent vasodilation (1,5). Other vasodilatory pathways include VEGF-stimulated COX-stimulated production of the vasodilator prostacyclin I 2 (1) VEGF also inhibits endothelial production of the potent vasoconstrictor endothelin-1 (ET-1) (6).…”

Section: A Primer In Vascular Biology and Signaling Of Vegfmentioning

confidence: 99%

“…In conscious rats the dose-dependent increase in sunitinib-induced BP elevation was associated with a dose-dependent decrease in urinary excretion of the NO effector molecule cGMP (24). However some clinical studies failed to show a role of decreased NO availability as an underlying cause of the vasoconstriction and BP rise caused by VEGFIs (5). …”

Section: Mechanism Of Hypertension During Vegf Inhibitionmentioning

confidence: 99%

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Recent Advances in Hypertension and Cardiovascular Toxicities With Vascular Endothelial Growth Factor Inhibition

et al. 2017

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Physiologically, vascular endothelial growth factors (VEGF) and their receptors (VEGFR) play a critical role in vascular development, neogenesis, angiogenesis, endothelial function and vascular tone. Pathologically, VEGF-VEGFR signaling induces dysregulated angiogenesis, which contributes to the growth and spread of tumors. The development of VEGF-VEGFR inhibitors (VEGFIs) has thus proven to be a valuable strategy in the management of a number of malignancies, yielding improved survival outcomes. Not surprisingly, VEGFIs are now standard of care as first-line monotherapy for some cancers and the scope of this class of drugs is growing. However with the promise of improved outcomes, VEGFIs also led to clinically relevant toxicities, especially hypertension and cardiovascular disease (CVD). As such, cancer patients treated with VEGFIs may have improved cancer outcomes, but at the cost of an increased risk of CVD. Indeed, dose intensity and protracted use of these drugs can be limited by cardiovascular side effects and patients may require dose reduction or drug withdrawal, thus compromising anti-cancer efficacy and survival. Here we summarize the vascular biology of VEGF-VEGFR signaling and discuss the cardiovascular consequences and clinical impact of VEGFIs. New insights into molecular mechanisms whereby VEGFIs cause hypertension and heart disease are highlighted.

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“…Однако в последнее время получила развитие концепция о критической роли сигналинга через рецептор VEGFR-2 для широкого спектра физиологических и патологических процессов, включая канцерогенез, сердечно-сосудистую патологию, офтальмологические проблемы [4]. Образование комплекса VEGFR/VEGFR-2 необходимо для активации основных звеньев морфогенеза сосудов -стимуляции пролиферации и миграции эндотелиальных клеток [2].…”

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ROLE OF VEGFR-2 (KDR/Flk-1) IN CARDIOMYOGENESIS AND CYTOPROTECTIVE REACTIONS

Meshkov¹,

Novoselova²,

Bushmanova³

et al. 2016

СПНО (MPSE)

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Представлены современные данные о роли рецептора-2 сосудистого эндотелиального фактора роста (VEGFR2, KDR/Flk-1) в кардиомиогенезе и цитопротекторных реакциях. Показано, что функционирование рецептора VEGFR-2 на протяжении эмбриогенеза является критическим для развития организмов, поскольку нокаут гена Flk-1, кодирующего белок-рецептор VEGFR-2, на ранних стадиях эмбриогенеза приводит к гибели эмбрионов мышей из-за недостаточного образования в зародыше гемопоэтических и эндотелиальных клеток и отсутствия нормально сформированных кровеносных сосудов. На более поздних стадиях эмбриогенеза доказано участие VEGFR-2 в формировании предсердно-желудочковых клапанов сердца. Усиление регенераторного потенциала и кардиомиогенной направленности культивируемых мезенхимальных стволовых клеток достигается путем повышения в них экспрессии VEGFR-2. В экспериментах на крысах показано, что введение животным таких клеток предотвращает выраженные постинфарктные структурные изменения левого желудочка. Усиление экспрессии VEGFR-2 в кардиомиоцитах выявлено и в других моделях повреждения миокарда, в частности при моделировании антрациклиновой кардиомиопатии. Ключевые слова: миокард, кардиомиогенез, регенерация, VEGFR-2/KDR/Flk-1, клеточная терапия ROLE OF VEGFR-2 (KDR/Flk-1) IN CARDIOMYOGENESIS AND CYTOPROTECTIVE REACTIONS Meshkov I.O., Novoselova E.I., Bushmanova G.M., Semenov D.E. Institute of Molecular Pathology and Pathomorphology, Novosibirsk, e-mail: pathol@inbox.ruContemporary data on the role of vascular endothelial growth factor receptor-2 (VEGFR2, KDR/Flk-1) in cardiomyogenesis and cytoprotective reactions are presented. It is shown that the functioning of VEGFR-2 during embryogenesis is critical for the development of organisms, since the Flk-1 gene knockout in the early stages of embryogenesis leads to the death of mouse embryos due to the lack of formation of hematopoietic and endothelial cells in the fetus and the absence of normally formed blood vessels. In the later stages of embryogenesis the involvement of VEGFR-2 in the formation of the atrioventricular valves of the heart was proved. Enhancing the regenerative potential and cardiomyogenic lineage of cultured mesenchymal stem cells is done by increasing in them the expression of VEGFR-2. In experiments on rats it was shown that the injection of such cells into animals prevents post-infarction pronounced structural changes of the left ventricle. An increased expression of VEGFR-2 in cardiomyocytes also was identified in other models of myocardial damage, in particular, when modeling anthracycline cardiomyopathy.

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Modulation of VEGF receptor 2 signaling by protein phosphatases

Cited by 45 publications

References 266 publications

VEGFR1 and VEGFR2 in Alzheimer’s Disease

VEGFR1 and VEGFR2 in Alzheimer’s Disease

Recent Advances in Hypertension and Cardiovascular Toxicities With Vascular Endothelial Growth Factor Inhibition

ROLE OF VEGFR-2 (KDR/Flk-1) IN CARDIOMYOGENESIS AND CYTOPROTECTIVE REACTIONS

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