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Am J Pathol. 2014 May;184(5):1562-76. doi: 10.1016/j.ajpath.2014.01.009. Epub 2014 Mar 5.

Ceramide-activated phosphatase mediates fatty acid-induced endothelial VEGF resistance and impaired angiogenesis.

Author information

1
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut; Department of Immunobiology, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut; Raymond and Beverly Sackler Foundation Cardiovascular Laboratory, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut.
2
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut.
3
SUNY Downstate Medical Center, Brooklyn, New York.
4
Department of Pharmacology, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut.
5
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut; Howard Hughes Medical Institute, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut.
6
Department of Internal Medicine, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut; Department of Immunobiology, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut; Raymond and Beverly Sackler Foundation Cardiovascular Laboratory, Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut. Electronic address: jeffrey.bender@yale.edu.

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.

PMID:
24606881
PMCID:
PMC4005977
DOI:
10.1016/j.ajpath.2014.01.009
[Indexed for MEDLINE]
Free PMC Article

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