1,721,149 research outputs found
CD93 maintains endothelial barrier function by limiting the phosphorylation and turnover of VE-cadherin
Full text linkRegulation of vascular permeability to plasma is essential for tissue and organ homeostasis and is mediated by endothelial cell-to-cell junctions that tightly regulate the trafficking of molecules between blood and tissue. The single-pass transmembrane glycoprotein CD93 is upregulated in endothelial cells during angiogenesis and controls cytoskeletal dynamics. However, its role in maintaining homeostasis by regulating endothelial barrier function has not been elucidated yet. Here, we demonstrate that CD93 interacts with vascular endothelial (VE)-cadherin and limits its phosphorylation and turnover. CD93 deficiency in vitro and in vivo induces phosphorylation of VE-cadherin under basal conditions, displacing it from endothelial cell–cell contacts. Consistent with this, endothelial junctions are defective in CD93−/− mice, and the blood–brain barrier permeability is enhanced. Mechanistically, CD93 regulates VE-cadherin phosphorylation and turnover at endothelial junctions through the Rho/Rho kinase-dependent pathway. In conclusion, our results identify CD93 as a key regulator of VE-cadherin stability at endothelial junctions, opening up possibilities for therapeutic strategies directed to control vascular permeability
Endothelial cell-specific phosphatase VE-PTP in regulation of endothelial biology
Full text linkVascular endothelial growth factor (VEGF)-A signal transduction is a central mediator of
angiogenesis in development and in pathological conditions, such as ischemic retinopathies. The role
of VEGFA in pathophysiological processes including neovascularization and vascular permeability, and
the therapeutic benefit of targeting VEGFA and its main receptor on endothelial cells, VEGF receptor 2 (VEGFR2), has been well documented. However, the significant treatment burden for the patient and
the transient efficacy of anti-VEGF/VEGFR2 drugs in retinal vascular diseases create a need for new
therapeutic targets to improve the diseases´ outcome. Vascular endothelial protein tyrosine
phosphatase (VE-PTP, also known as PTPRB) is an endothelial specific tyrosine phosphate that interacts
with VEGFR2 and Tie2, thereby regulating their activity. Here, we evaluated the efficiency of a siRNA
targeting human PTPRB and identified commercially available antibodies specific for VE-PTP to be used
in in vitro studies. Immunofluorescence analyses of human umbilical vein endothelial cells showed
colocalization of VE-PTP with vascular endothelial (VE)-cadherin at endothelial cell junctions, where
VE-PTP is known to interact with VEGFR2, Tie2 and VE-cadherin. Silencing of PTPRB expression in vitro
was accompanied by increased VEGFA-induced VEGFR2 phosphorylation at tyrosine site 1175, which
unexpectedly was accompanied by decreased phosphorylation of the downstream extracellular
regulated kinase (Erk) 1/2. Moreover, endothelial specific genetic deletion of the murine VE-PTP
codifying gene, denoted Ptprb, impaired retina vascular development, negatively affecting retina
vessel density, vessel outgrowth and tip cell density. These effects on the retina vasculature did not
depend on changes in expression levels of Flk1, Tie2 or Cdh5. In a mouse model of oxygen-induced
retinopathy (OIR), genetic Ptprb deficiency reduced vessel obliteration but had no effect on formation
of neovascular tufts. In conclusion, we demonstrate that VE-PTP is required in vivo for normal
development of the retinal vasculature and inhibition of PTPRB expression in vitro markedly enhances
VEGFR2 phosphorylation in response to VEGFA while subsequent activation of its downstream
signalling transducer Erk 1/2 is suppressed. This suggests a potential mechanism by which targeting
VE-PTP may reduce vessel obliteration observed in ischemic eye diseases. However, more in-depth
analyses are warranted.A transdução de sinal do vascular endothelial growth factor (VEGF)-A é um dos principais
mediadores da angiogénese durante o desenvolvimento e em condições patológicas como retinopatias
isquémicas. O papel do VEGFA em processos fisiopatológicos, incluindo a neovascularização e a
permeabilidade vascular, e o benefício de terapias que têm como alvo o VEGFA e o seu recetor
principal nas células endoteliais, o VEGF recetor-2 (VEGFR2), tem sido bem documentados. Contudo,
a carga significativa do tratamento para o paciente e a eficácia transitória dos medicamentos anti VEGF/VEGFR2 em doenças vasculares da retina criam a necessidade de novos alvos terapêuticos para
melhorar o resultado do tratamento. A vascular endothelial protein tyrosine phosphatase (VE-PTP,
também conhecida como PTPRB) é uma fosfatase de tirosinas, especificamente expressa em células
endoteliais, que interage com o VEGFR2 e o Tie2, regulando assim a atividade destes. Neste trabalho,
avaliámos a eficiência de um siRNA direcionado ao PTPRB humano e identificámos anticorpos
comerciais específicos para a VEPTP para serem usados em estudos in vitro. Análises de
imunofluorescência de células endoteliais da veia umbilical humana revelaram que a VE-PTP se localiza
com a vascular endothelial (VE)-cadherin nas junções de células endoteliais, onde se sabe que a VE PTP interage com o VEGFR2, Tie2 e VE-cadherin. O silenciamento da expressão do PTPRB in vitro
aumentou a fosforilação do VEGFR2, induzida pelo VEGFA, na tirosina 1175, o qual inesperadamente
foi acompanhado por uma diminuição na fosforilação da extracellular regulated kinase (Erk) 1/2. Além
disso, a deleção genética do gene que codifica a VE-PTP, denominado Ptprb, em células endoteliais
prejudicou o desenvolvimento vascular na retina afetando negativamente a densidade vascular, o
crescimento vascular e a densidade de tip cells na retina. Estes efeitos na vasculatura da retina não
dependem de mudanças nos níveis de expressão de Flk1, Tie2 ou Cdh5. Num modelo de ratinho de
retinopatia induzida com oxigénio (OIR), a deficiência genética do Ptprb reduziu a obliteração da
vasculatura, mas não afetou a formação de tufts neovasculares. Concluindo, neste trabalho
demonstramos que a VE-PTP é necessária in vivo para o normal desenvolvimento da vasculatura da
retina e que a inibição da expressão de PTPRB in vitro aumenta significativamente a fosforilação do
VEGFR2 em resposta ao VEGFA enquanto que a subsequente ativação do seu transdutor de sinalização
downstream Erk 1/2 é suprimida. Isto sugere um potencial mecanismo pelo qual ter como alvo a VE PTP pode reduzir a obliteração dos vasos sanguíneos observada em doenças isquémicas dos olhos.
Contudo, análises mais aprofundadas são necessárias
Oxygen sensing : a stunningly elegant molecular machinery highjacked in cancer
No full textOxygen is of fundamental importance for most living organisms, and the maintenance of oxygen homeostasis is a key physiological challenge for all large animals. Oxygen deprivation, hypoxia, is a critical component of many human diseases including cancer, heart disease, stroke, vascular disease, and anaemia. The discovery of oxygen sensing provides fundamental knowledge of a stunningly elegant molecular machinery; it also promises development of new therapeutics for serious diseases such as cancer. As a result of their impressive contributions to our understanding of the mechanisms by which cells sense oxygen and signal in hypoxia, Gregg Semenza, Peter Ratcliffe, and William Kaelin were awarded the Nobel Prize in 2019
Receptor Talk and Tumor Cell Walk in Glioblastoma
No full textIn this issue of Cancer Cell, Lu et al. describe unconventional molecular interactions in glioblastoma cells that provide a mechanism for how anti-vascular endothelial growth factor therapy may promote mesenchymal transition of glioblastoma cells and increase tumor invasion
What is normal? : Apelin and VEGFA, drivers of tumor vessel abnormality
No full textIn this issue of EMBO Molecular Medicine, Uribesalgo and coworkers show that high Apelin expression correlates with poor survival in advanced breast (MMTV-NeuT) and lung (KRASG12D) murine tumor models as well as in breast and lung cancer in humans. Combining Apelin inhibition (genetically or using an inactive Apelin agonist) with anti-angiogenic therapy using different small molecular weight kinase inhibitors (sunitinib, axitinib) led to marked delay in breast cancer growth in mice. The vasculature in Apelin-targeted cancer showed normalized features including improved perfusion and reduced leakage. These important data provide a strong incentive to target Apelin in human cancer treatment
VEGFA and tumour angiogenesis
No full textIn this review we summarize the current understanding of signal transduction downstream of vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2, and the relationship between these signal transduction pathways and the hallmark responses of VEGFA, angiogenesis and vascular permeability. These physiological responses involve a number of effectors, including extracellular signal-regulated kinases (ERKs), Src, phosphoinositide 3 kinase (PI3K)/Akt, focal adhesion kinase (FAK), Rho family GTPases, endothelial NO and p38 mitogen-activated protein kinase (MAPK). Several of these factors are involved in the regulation of both angiogenesis and vascular permeability. Tumour angiogenesis primarily relies on VEGFA-driven responses, which to a large extent result in a dysfunctional vasculature. The reason for this remains unclear, although it appears that certain aspects of the VEGFA-stimulated angiogenic milieu (high level of microvascular density and permeability) promote tumour expansion. The high degree of redundancy and complexity of VEGFA-driven tumour angiogenesis may explain why tumours commonly develop resistance to anti-angiogenic therapy targeting VEGFA signal transduction.The definitive version is available at www.blackwell-synergy.com</p
Association of class II histocompatibility antigens with an invariant molecule, implications for intracellular transport
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Alk1 (Activin Receptor-Like Kinase 1) and Vascular Hyperpermeability in Diabetic Retinopathy : More Is Less
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