ArticleThe American journal of pathology2014
Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis.
Article in The American journal of pathology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers.
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Who cites it
36 citing papers in PubMed, 54 citations in OpenAlex.
- Curcumin as a ceramide metabolism-targeting agent: Molecular mechanisms and therapeutic implications in cancer.Molecular biology reports · 2026Review
- Identification of biomarkers for renal cell carcinoma in plasma samples measured using liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry.Scientific reports · 2025Article
- Multifunctional Dermatological Effects of Whole-PlantCurrent issues in molecular biology · 2025Article
- Defective lymphatic vasculature in obesity.Obesity reviews : an official journal of the International Association for the Study of Obesity · 2025Review
- Suppression of endothelial ceramide de novo biosynthesis by Nogo-B contributes to cardiometabolic diseases.Nature communications · 2025Article
- Elevated Very-Long-Chain Ceramides in the Vitreous Humor of Patients With Proliferative Diabetic Retinopathy.Investigative ophthalmology & visual science · 2025Article
- Free Fatty Acids and Free Fatty Acid Receptors: Role in Regulating Arterial Function.International journal of molecular sciences · 2024Review
- Endothelial Dysfunction in Obesity and Therapeutic Targets.Advances in experimental medicine and biology · 2024Review
- Coronary Event Risk Test (CERT) as a Risk Predictor for the 10-Year Clinical Outcome of Patients with Peripheral Artery Disease.Journal of clinical medicine · 2023Article
- Sphingolipids and Atherosclerosis: The Dual Role of Ceramide and Sphingosine-1-Phosphate.Antioxidants (Basel, Switzerland) · 2023Review
- Effects of sphingolipid metabolism disorders on endothelial cells.Lipids in health and disease · 2022Review
- S1PR1 induces metabolic reprogramming of ceramide in vascular endothelial cells, affecting hepatocellular carcinoma angiogenesis and progression.Cell death & disease · 2022Article
- Targeting Anti-Angiogenic VEGFCells · 2022Article
- Novel Insight into the Serum Sphingolipid Fingerprint Characterizing Longevity.International journal of molecular sciences · 2022Article
- Sphingolipid Metabolism and Signaling in Endothelial Cell Functions.Advances in experimental medicine and biology · 2022Review
- Article
- Activating transcription factor 4 regulates angiogenesis under lipid overload via methionine adenosyltransferase 2A-mediated endothelial epigenetic alteration.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Ceramide-Induced Lysosomal Biogenesis and Exocytosis in Early-Onset Preeclampsia Promotes Exosomal Release of SMPD1 Causing Endothelial Dysfunction.Frontiers in cell and developmental biology · 2021Article
- Endothelial Sphingolipid De Novo Synthesis Controls Blood Pressure by Regulating Signal Transduction and NO via Ceramide.Hypertension (Dallas, Tex. : 1979) · 2020Article
- Tricyclic antidepressant amitriptyline inhibits autophagic flux and prevents tube formation in vascular endothelial cells.Basic & clinical pharmacology & toxicology · 2019Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
Abstract
Endothelial dysfunction, including endothelial hyporesponsiveness to prototypical angiogenic growth factors and eNOS agonists, underlies vascular pathology in many dysmetabolic states. We investigated effects of a saturated free fatty acid, palmitic acid (PA), on endothelial cell responses to VEGF. PA-pretreated endothelial cells had markedly diminished Akt, eNOS, and ERK activation responses to VEGF, despite normal VEGFR2 phosphorylation. PA inhibited VEGF-induced angiogenic cord formation in Matrigel, and PA-treated endothelial cells accumulated early species (C16) ceramide. The serine palmitoyltransferase inhibitor myriocin reversed these defects. Protein phosphatase 2A (PP2A) became more eNOS-associated in PA-treated cells; the PP2A inhibitor okadaic acid reversed PA-induced signaling defects. Mice fed a diet high in saturated fat for 2 to 3 weeks had impaired i) aortic Akt and eNOS phosphorylation to infused VEGF, ii) ear angiogenic responses to intradermal adenoviral-VEGF injection, and iii) vascular flow recovery to hindlimb ischemia as indicated by laser Doppler and αVβ3 SPECT imaging. High-fat feeding did not impair VEGF-induced signaling or angiogenic responses in mice with reduced serine palmitoyltransferase expression. Thus, de novo ceramide synthesis is required for these detrimental PA effects. The findings demonstrate an endothelial VEGF resistance mechanism conferred by PA, which comprises ceramide-induced, PP2A-mediated dephosphorylation of critical activation sites on enzymes central to vascular homeostasis and angiogenesis. This study defines potential molecular targets for preservation of endothelial function in metabolic syndrome.
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