Abstract
Aberrant blood vessel formation contributes to a wide variety of pathologies, and factors that regulate angiogenesis are attractive therapeutic targets. Endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) is a neuropilin-related transmembrane protein expressed in ECs; however, its potential effect on VEGF responses remains undefined. Here, we generated global and EC-specific Esdn knockout mice and demonstrated that ESDN promotes VEGF-induced human and murine EC proliferation and migration. Deletion of Esdn in the mouse interfered with adult and developmental angiogenesis, and knockdown of the Esdn homolog (dcbld2) in zebrafish impaired normal vascular development. Loss of ESDN in ECs blunted VEGF responses in vivo and attenuated VEGF-induced VEGFR-2 signaling without altering VEGF receptor or neuropilin expression. Finally, we found that ESDN associates with VEGFR-2 and regulates its complex formation with negative regulators of VEGF signaling, protein tyrosine phosphatases PTP1B and TC-PTP, and VE-cadherin. These findings establish ESDN as a regulator of VEGF responses in ECs that acts through a mechanism distinct from neuropilins. As such, ESDN may serve as a therapeutic target for angiogenesis regulation.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antigens, CD / physiology
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Blood Vessels / embryology
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Cadherins / physiology
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Cells, Cultured
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Ear, External / blood supply
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Endothelium, Vascular / physiology*
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Hindlimb / blood supply
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Human Umbilical Vein Endothelial Cells / metabolism
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Humans
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Ischemia / physiopathology
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Membrane Proteins / genetics
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Membrane Proteins / physiology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neovascularization, Physiologic / physiology*
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Neuropilins / physiology
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Protein Tyrosine Phosphatase, Non-Receptor Type 1 / physiology
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Protein Tyrosine Phosphatase, Non-Receptor Type 2 / physiology
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RNA Interference
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RNA, Small Interfering / pharmacology
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Retinal Vessels / growth & development
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Vascular Endothelial Growth Factor A / physiology*
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Vascular Endothelial Growth Factor Receptor-2 / physiology
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Zebrafish / embryology
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Zebrafish / genetics
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Zebrafish Proteins / physiology
Substances
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Antigens, CD
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Cadherins
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DCBLD2 protein, human
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Membrane Proteins
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Neuropilins
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RNA, Small Interfering
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Vascular Endothelial Growth Factor A
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Zebrafish Proteins
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cadherin 5
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Vascular Endothelial Growth Factor Receptor-2
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PTPN1 protein, human
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PTPN2 protein, human
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Protein Tyrosine Phosphatase, Non-Receptor Type 1
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Protein Tyrosine Phosphatase, Non-Receptor Type 2
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Ptpn1 protein, mouse
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Ptpn2 protein, mouse