ArticleThe Journal of clinical investigation2023
Endothelial VEGFR2-PLCγ signaling regulates vascular permeability and antitumor immunity through eNOS/Src.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 43 citations in OpenAlex.
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- Shock Induced Endotheliopathy and High Trauma Mortality-Fight-or-Flight Response Revisited.International journal of molecular sciences · 2026Review
- Reimagining VEGF Therapy: The Role of PLCγ2 in Pan-Organ Endothelial Networks.Advances in wound care · 2026Article
- Soluble TREM2 engages cell-surface nucleolin to drive vascular permeability and malignant ascites in ovarian cancer.EMBO molecular medicine · 2026Article
- SRC as a Prognostic and Immunomodulatory Biomarker in Acute Myeloid Leukemia: A Multi-Omics Study.International journal of molecular sciences · 2026Article
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- Modulating Vimentin: A Systems-Level Therapeutic Strategy for Sepsis and Complex Diseases.Life (Basel, Switzerland) · 2026Article
- Reduced vascular leakage correlates with breast carcinoma T regulatory cell infiltration but not with metastatic propensity.Molecular oncology · 2026Article
- SHP2 regulates VEGFR2 Y1175/PLCγ signaling to impair tumor endothelial barrier stability.iScience · 2026Article
- Propofol attenuates angiogenesis by activating endoplasmic reticulum stress to suppress TFAP2C-driven VEGFA transcription.Apoptosis : an international journal on programmed cell death · 2026Article
- Obesity-driven metabolic reprogramming and immune dysfunction in renal cancer.Frontiers in immunology · 2026Review
- Exploring the antiangiogenic effects of Phospholipases ACell and tissue research · 2025Article
- Endothelial-Pericyte Interactions Regulate Angiogenesis Via VEGFR2 Signaling During Retinal Development and Disease.Investigative ophthalmology & visual science · 2025Article
- Inhibition of Endothelial HIF-1α by IDF-11774 Attenuates Retinal Neovascularization and Vascular Leakage.Investigative ophthalmology & visual science · 2025Article
- Advances in the molecular signaling mechanisms of VEGF/VEGFR2 in fundus neovascularization disease (Review).Experimental and therapeutic medicine · 2025Review
- Vascular endothelial growth factor signaling in health and disease: from molecular mechanisms to therapeutic perspectives.Signal transduction and targeted therapy · 2025Review
- Targeting vascular endothelial growth receptor-2 (VEGFR-2): structural biology, functional insights, and therapeutic resistance.Archives of pharmacal research · 2025Review
- Scaffold-free endocrine tissue engineering: role of islet organization and implications in type 1 diabetes.BMC endocrine disorders · 2025Review
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Authors and funding
14 authors at 3 institutions in 3 countries.
Funding
Abstract
Endothelial phospholipase Cγ (PLCγ) is essential for vascular development; however, its role in healthy, mature, or pathological vessels is unexplored. Here, we show that PLCγ was prominently expressed in vessels of several human cancer forms, notably in renal cell carcinoma (RCC). High PLCγ expression in clear cell RCC correlated with angiogenic activity and poor prognosis, while low expression correlated with immune cell activation. PLCγ was induced downstream of vascular endothelial growth factor receptor 2 (VEGFR2) phosphosite Y1173 (pY1173). Heterozygous Vegfr2Y1173F/+ mice or mice lacking endothelial PLCγ (Plcg1iECKO) exhibited a stabilized endothelial barrier and diminished vascular leakage. Barrier stabilization was accompanied by decreased expression of immunosuppressive cytokines, reduced infiltration of B cells, helper T cells and regulatory T cells, and improved response to chemo- and immunotherapy. Mechanistically, pY1173/PLCγ signaling induced Ca2+/protein kinase C-dependent activation of endothelial nitric oxide synthase (eNOS), required for tyrosine nitration and activation of Src. Src-induced phosphorylation of VE-cadherin at Y685 was accompanied by disintegration of endothelial junctions. This pY1173/PLCγ/eNOS/Src pathway was detected in both healthy and tumor vessels in Vegfr2Y1173F/+ mice, which displayed decreased activation of PLCγ and eNOS and suppressed vascular leakage. Thus, we believe that we have identified a clinically relevant endothelial PLCγ pathway downstream of VEGFR2 pY1173, which destabilizes the endothelial barrier and results in loss of antitumor immunity.
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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.