ArticleProceedings of the National Academy of Sciences of the United States of America2014
VEGF-induced neoangiogenesis is mediated by NAADP and two-pore channel-2-dependent Ca2+ signaling.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 105 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
105 citing papers in PubMed, 157 citations in OpenAlex.
- Inhibition of endolysosomal two-pore channel 2 (TPC2) induces osteoblast differentiation and matrix mineralization while targeting autophagy.Journal of endocrinological investigation · 2026Article
- Lysosomal channel TPC2 modulates microglia-endothelial signaling in choroidal angiogenesis.Angiogenesis · 2026Article
- TPC2 regulates proteomic remodeling, bioenergetic phenotypes, and mitochondrial stress adaptation in melanoma.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2026Article
- NAADP elicits two-pore channel currents by lifting Lsm12-mediated inhibition of PI(3,5)PbioRxiv : the preprint server for biology · 2026Article
- Review
- NMRK2 leads to the depletion of CD8Oncogene · 2025Article
- The Two-Pore Channel 2 in Human Physiology and Diseases: Functional Characterisation and Pharmacology.International journal of molecular sciences · 2025Review
- The Calcium Signalling Profile of the Inner Blood-Retinal Barrier in Diabetic Retinopathy.Cells · 2025Review
- XPNPEP2 regulates angiogenesis via modulation of mitochondrial function through SLC25A6.Frontiers in cell and developmental biology · 2025Article
- Loss of two-pore channel 2 enhances CD8+ T cell cytotoxicity and directly impairs tumour growth via MAPK axis in HCC.Frontiers in immunology · 2025Article
- Terahertz Irradiation Promotes Angiogenesis in vitro by Enhancing Permeability of the Voltage-Gated Calcium Channel.PloS one · 2025Article
- The ion channels of endomembranes.Physiological reviews · 2024Review
- Whole-exome sequencing identifies cancer-associated variants of the endo-lysosomal ion transport channels in the Saudi population.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2024Article
- Lysosomal TRPML1 triggers global CaFrontiers in physiology · 2024Article
- Targeting Lysosomes: A Strategy Against Chemoresistance in Cancer.Mini reviews in medicinal chemistry · 2024Review
- Endolysosomal transient receptor potential mucolipins and two-pore channels: implications for cancer immunity.Frontiers in immunology · 2024Review
- Loss of two-pore channel 2 function in melanoma-derived tumours reduces tumour growth in vivo but greatly increases tumour-related toxicity in the organism.Cancer cell international · 2023Article
- Cracking the Endothelial Calcium (CaInternational journal of molecular sciences · 2023Review
- Mitochondria in endothelial cells angiogenesis and function: current understanding and future perspectives.Journal of translational medicine · 2023Review
- Conformational rearrangements in the second voltage sensor domain switch PIPProceedings of the National Academy of Sciences of the United States of America · 2023Article
45 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 2 countries.
Funding
Abstract
Vascular endothelial growth factor (VEGF) and its receptors VEGFR1/VEGFR2 play major roles in controlling angiogenesis, including vascularization of solid tumors. Here we describe a specific Ca(2+) signaling pathway linked to the VEGFR2 receptor subtype, controlling the critical angiogenic responses of endothelial cells (ECs) to VEGF. Key steps of this pathway are the involvement of the potent Ca(2+) mobilizing messenger, nicotinic acid adenine-dinucleotide phosphate (NAADP), and the specific engagement of the two-pore channel TPC2 subtype on acidic intracellular Ca(2+) stores, resulting in Ca(2+) release and angiogenic responses. Targeting this intracellular pathway pharmacologically using the NAADP antagonist Ned-19 or genetically using Tpcn2(-/-) mice was found to inhibit angiogenic responses to VEGF in vitro and in vivo. In human umbilical vein endothelial cells (HUVECs) Ned-19 abolished VEGF-induced Ca(2+) release, impairing phosphorylation of ERK1/2, Akt, eNOS, JNK, cell proliferation, cell migration, and capillary-like tube formation. Interestingly, Tpcn2 shRNA treatment abolished VEGF-induced Ca(2+) release and capillary-like tube formation. Importantly, in vivo VEGF-induced vessel formation in matrigel plugs in mice was abolished by Ned-19 and, most notably, failed to occur in Tpcn2(-/-) mice, but was unaffected in Tpcn1(-/-) animals. These results demonstrate that a VEGFR2/NAADP/TPC2/Ca(2+) signaling pathway is critical for VEGF-induced angiogenesis in vitro and in vivo. Given that VEGF can elicit both pro- and antiangiogenic responses depending upon the balance of signal transduction pathways activated, targeting specific VEGFR2 downstream signaling pathways could modify this balance, potentially leading to more finely tailored therapeutic strategies.
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Registered trials
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.