Abstract
Chronic alterations in blood flow initiate structural changes in vessel lumen caliber to normalize shear stress. The loss of endothelial derived nitric oxide synthase (eNOS) in mice promotes abnormal flow dependent vascular remodeling, thus uncoupling mechanotransduction from adaptive vascular remodeling. However, the mechanisms of how the loss of eNOS promotes abnormal remodeling are not known. Here we show that abnormal flow-dependent remodeling in eNOS knockout mice (eNOS (-/-)) is associated with activation of the platelet derived growth factor (PDGF) signaling pathway leading to the induction of the inhibitor of apoptosis, survivin. Interfering with PDGF signaling or survivin function corrects the abnormal remodeling seen in eNOS (-/-) mice. Moreover, nitric oxide (NO) negatively regulates PDGF driven survivin expression and cellular proliferation in cultured vascular smooth muscle cells. Collectively, our data suggests that eNOS negatively regulates the PDGF-survivin axis to maintain proportional flow-dependent luminal remodeling and vascular quiescence.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis
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Blood Vessels / physiopathology*
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Blotting, Western
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Cell Proliferation
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Cells, Cultured
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Endothelium, Vascular / cytology
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Endothelium, Vascular / metabolism*
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Immunoenzyme Techniques
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Inhibitor of Apoptosis Proteins / genetics
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Inhibitor of Apoptosis Proteins / metabolism*
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Male
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Mechanotransduction, Cellular / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / metabolism*
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Neovascularization, Physiologic / physiology*
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Nitric Oxide / metabolism
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Nitric Oxide Synthase Type III / physiology*
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Platelet-Derived Growth Factor / genetics
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Platelet-Derived Growth Factor / metabolism*
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Protein Binding
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RNA, Messenger / genetics
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Real-Time Polymerase Chain Reaction
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Signal Transduction
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Survivin
Substances
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Birc5 protein, mouse
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Inhibitor of Apoptosis Proteins
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Platelet-Derived Growth Factor
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RNA, Messenger
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Repressor Proteins
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Survivin
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platelet-derived growth factor A
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Nitric Oxide
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Nitric Oxide Synthase Type III
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Nos3 protein, mouse