title: EGFL7 ligates αvβ3 integrin to enhance vessel formation.
abstract: Angiogenesis, defined as blood vessel formation from a preexisting vasculature, is governed by multiple signal cascades including integrin receptors, in particular integrin αVβ3. Here we identify the endothelial cell (EC)-secreted factor epidermal growth factor-like protein 7 (EGFL7) as a novel specific ligand of integrin αVβ3, thus providing mechanistic insight into its proangiogenic actions in vitro and in vivo. Specifically, EGFL7 attaches to the extracellular matrix and by its interaction with integrin αVβ3 increases the motility of EC, which allows EC to move on a sticky underground during vessel remodeling. We provide evidence that the deregulation of EGFL7 in zebrafish embryos leads to a severe integrin-dependent malformation of the caudal venous plexus, pointing toward the significance of EGFL7 in vessel development. In biopsy specimens of patients with neurologic diseases, vascular EGFL7 expression rose with increasing EC proliferation. Further, EGFL7 became upregulated in vessels of the stroke penumbra using a mouse model of reversible middle cerebral artery occlusion. Our data suggest that EGFL7 expression depends on the remodeling state of the existing vasculature rather than on the phenotype of neurologic disease analyzed. In sum, our work sheds a novel light on the molecular mechanism EGFL7 engages to govern physiological and pathological angiogenesis.
authors: Molecular Signal Transduction Laboratory at the Institute of Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Johannes Gutenberg University School of Medicine, Mainz, Germany.
authors: Iva
authors: I
authors: Nikolic
authors: Nevenka Dudvarski
authors: ND
authors: Stankovic
authors: Frank
authors: F
authors: Bicker
authors: Jeannette
authors: J
authors: Meister
authors: Helene
authors: H
authors: Braun
authors: Khader
authors: K
authors: Awwad
authors: Jan
authors: J
authors: Baumgart
authors: Kirsten
authors: K
authors: Simon
authors: Serge C
authors: SC
authors: Thal
authors: Chinmoy
authors: C
authors: Patra
authors: Patrick N
authors: PN
authors: Harter
authors: Karl H
authors: KH
authors: Plate
authors: Felix B
authors: FB
authors: Engel
authors: Stefanie
authors: S
authors: Dimmeler
authors: Johannes A
authors: JA
authors: Eble
authors: Michel
authors: M
authors: Mittelbronn
authors: Michael K
authors: MK
authors: Schäfer
authors: Benno
authors: B
authors: Jungblut
authors: Emmanouil
authors: E
authors: Chavakis
authors: Ingrid
authors: I
authors: Fleming
authors: Mirko H H
authors: MHH
authors: Schmidt
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D001808:Blood Vessels / Q000378:metabolism*; D002135:Calcium-Binding Proteins; D002448:Cell Adhesion / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D066255:EGF Family of Proteins; D004625:Embryo, Nonmammalian / Q000098:blood supply / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015027:Zebrafish
chemical_list: D002135:Calcium-Binding Proteins; D066255:EGF Family of Proteins; C527877:EGFL7 protein, human; D016228:Endothelial Growth Factors; D039302:Integrin alphaVbeta3