ArticleThe Journal of biological chemistry2011
Ca2+ influx through reverse mode Na+/Ca2+ exchange is critical for vascular endothelial growth factor-mediated extracellular signal-regulated kinase (ERK) 1/2 activation and angiogenic functions of human endothelial cells.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
48 citing papers in PubMed, 72 citations in OpenAlex.
- The Dual Role of VEGF in Intracerebral Haemorrhage: From Pathological Mechanisms to Therapeutic Opportunities.Revista de neurologia · 2026Review
- Voltage-Dependent Ion Channels in Vascular Endothelial Cells: An Unexpected Signaling Pathway in Non-Excitable Cells.Biomedicines · 2026Review
- Functional Coupling Between Voltage-Dependent Sodium Channels and Activation of the CaInternational journal of molecular sciences · 2026Article
- SECS, drugs, and Rac1&Rho: regulation of EnNaC in vascular endothelial cells.Pflugers Archiv : European journal of physiology · 2025Article
- The generation of stable microvessels in ischemia is mediated by endothelial cell derived TRAIL.Science advances · 2024Article
- A TRP to Pathological Angiogenesis and Vascular Normalization.Comprehensive Physiology · 2024Review
- Store-Operated CaJournal of clinical medicine · 2023Review
- NCX2 Regulates Intracellular Calcium Homeostasis and Translocation of HIF-1α into the Nucleus to Inhibit Glioma Invasion.Biochemical genetics · 2023Article
- Pharmacologic modulation of intracellular NaProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Activation of Coronary Arteriolar PKCβ2 Impairs Endothelial NO-Mediated Vasodilation: Role of JNK/Rho Kinase Signaling and Xanthine Oxidase Activation.International journal of molecular sciences · 2021Article
- CaCancers · 2021Review
- A guide to plasma membrane solute carrier proteins.The FEBS journal · 2021Review
- Breast cancer therapy affects the expression of antineonatal Nav1.5 antibodies in the serum of patients with breast cancer.Oncology letters · 2021Article
- Impact of Na+ permeation on collective migration of pulmonary arterial endothelial cells.PloS one · 2021Article
- Genome-wide association study of the TP53 R249S mutation in hepatocellular carcinoma with aflatoxin B1 exposure and infection with hepatitis B virus.Journal of gastrointestinal oncology · 2020Article
- Endogenous cardiotonic steroids and cardiovascular disease, where to next?Cell calcium · 2020Review
- Sodium Transporters in Human Health and Disease.Frontiers in physiology · 2020Review
- Endothelial CaInternational journal of molecular sciences · 2019Review
- Cyclosporine A sensitizes lung cancer cells to crizotinib through inhibition of the Ca2EBioMedicine · 2019Article
- Honey-Mediated Wound Healing: H₂O₂ Entry through AQP3 Determines Extracellular CaInternational journal of molecular sciences · 2019Article
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Authors and funding
6 authors at 5 institutions in 2 countries.
Funding
Abstract
VEGF is a key angiogenic cytokine and a major target in anti-angiogenic therapeutic strategies. In endothelial cells (ECs), VEGF binds VEGF receptors and activates ERK1/2 through the phospholipase γ (PLCγ)-PKCα-B-Raf pathway. Our previous work suggested that influx of extracellular Ca(2+) is required for VEGF-induced ERK1/2 activation, and we hypothesized that this could occur through reverse mode (Ca(2+) in and Na(+) out) Na(+)-Ca(2+) exchange (NCX). However, the role of NCX activity in VEGF signaling and angiogenic functions of ECs had not previously been described. Here, using human umbilical vein ECs (HUVECs), we report that extracellular Ca(2+) is required for VEGF-induced ERK1/2 activation and that release of Ca(2+) from intracellular stores alone, in the absence of extracellular Ca(2+), is not sufficient to activate ERK1/2. Furthermore, inhibitors of reverse mode NCX suppressed the VEGF-induced activation of ERK1/2 in a time- and dose-dependent manner and attenuated VEGF-induced Ca(2+) transients. Knockdown of NCX1 (the main NCX isoform in HUVECs) by siRNA confirmed the pharmacological data. A panel of NCX inhibitors also significantly reduced VEGF-induced B-Raf activity and inhibited PKCα translocation to the plasma membrane and total PKC activity in situ. Finally, NCX inhibitors reduced VEGF-induced HUVEC proliferation, migration, and tubular differentiation in surrogate angiogenesis functional assays in vitro. We propose that Ca(2+) influx through reverse mode NCX is required for the activation and the targeting of PKCα to the plasma membrane, an essential step for VEGF-induced ERK1/2 phosphorylation and downstream EC functions in angiogenesis.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.