Migration Inhibitory Factor Mediates Angiogenesis via Mitogen-Activated Protein Kinase and Phosphatidylinositol Kinase

ABSTRACT—In this study, we investigated the effects of migration inhibitory factor (rhMIF) on angiogenesis-related signaling cascades and apoptosis in human endothelial cells (ECs). We show that in vitro rhMIF induces migration and tube formation in Matrigel of human dermal microvascular endothelial...

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Bibliographic Details
Published in:Circulation research 2003-08, Vol.93 (4), p.321-329
Main Authors: Amin, M Asif, Volpert, Olga V, Woods, James M, Kumar, Pawan, Harlow, Lisa A, Koch, Alisa E
Format: Article
Language:English
Subjects:
Angiogenesis Inducing Agents - pharmacology
Animals
Biological and medical sciences
Blood vessels and receptors
Cell Line
Cell Movement - drug effects
Chromones - pharmacology
Cornea - blood supply
DNA-Binding Proteins
Dose-Response Relationship, Drug
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Enzyme Inhibitors - pharmacology
ets-Domain Protein Elk-1
Flavonoids - pharmacology
Fundamental and applied biological sciences. Psychology
Humans
Macrophage Migration-Inhibitory Factors - pharmacology
Mice
Mice, Inbred C57BL
Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors
Mitogen-Activated Protein Kinase 1 - metabolism
Mitogen-Activated Protein Kinase 3
Mitogen-Activated Protein Kinases - antagonists & inhibitors
Mitogen-Activated Protein Kinases - genetics
Mitogen-Activated Protein Kinases - metabolism
Morpholines - pharmacology
Mutation
Neovascularization, Physiologic - drug effects
Oligonucleotides, Antisense - pharmacology
Phosphatidylinositol 3-Kinases - antagonists & inhibitors
Phosphatidylinositol 3-Kinases - metabolism
Phosphorylation
Protein-Serine-Threonine Kinases
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-akt
Rats
Recombinant Proteins - pharmacology
Signal Transduction - drug effects
Transcription Factors
Vertebrates: cardiovascular system
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Summary:ABSTRACT—In this study, we investigated the effects of migration inhibitory factor (rhMIF) on angiogenesis-related signaling cascades and apoptosis in human endothelial cells (ECs). We show that in vitro rhMIF induces migration and tube formation in Matrigel of human dermal microvascular endothelial cells (HMVECs), with potency comparable to that of basic fibroblast growth factor. In vivo, rhMIF induces angiogenesis in Matrigel plugs and in the corneal bioassay. Using panels of relatively specific kinase inhibitors, antisense oligonucleotides, and dominant-negative mutants, we show that mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K) are critical for MIF-dependent HMVEC migration, whereas Src and p38 kinases are nonessential. Moreover, we demonstrate that rhMIF induces time-dependent increases in phosphorylation levels of MEK1/2, Erk1/2, and Elk-1, as well as PI3K, and its effector kinase, Akt, in HMVECs. Studies with dominant-negative mutants and antisense oligonucleotides corroborate these effects in HMVECs. Furthermore, we demonstrate that rhMIF-induced angiogenesis in the rat cornea in vivo and in the ex vivo endothelial cell morphogenesis assay is also MAPK- and PI3K-dependent. Our findings support a role for MIF as an angiogenic factor and provide a rationale for the use of MIF as a therapeutic inducer of neovascularization in the development of collateral circulation in coronary artery disease.
ISSN:0009-7330
1524-4571
DOI:10.1161/01.RES.0000087641.56024.DA