Regulation of neovascularization by human neutrophil peptides (alpha-defensins): a link between inflammation and angiogenesis.
Angiogenesis, the growth of new blood vessels, is a complex biological process that is orchestrated by several growth factors and components of the extracellular matrix, including fibronectin (FN) and its receptor the integrin alpha5beta1. Angiogenesis is a critical part of inflammation and wound repair, but the mechanism by which vascular proliferation and migration is regulated by inflammatory cells is not completely understood. We have previously shown that human neutrophil peptides (HNPs), also known as alpha-defensins, which are secreted in high concentrations when neutrophils are activated, bind specifically to FN in the extracellular matrix and inhibit plasminogen activation. Therefore, we asked whether HNPs act as a link between inflammation and angiogenesis. Alpha5beta1-mediated endothelial cell adhesion and migration to FN, both under control conditions and under stimulation by vascular endothelial growth factor (VEGF), were inhibited specifically and in a dose-dependent manner by HNPs, whereas endothelial cell adhesion and migration to other components of the extracellular matrix, such as vitronectin, collagen, or fibrinogen/fibrin were not. Consistent with this finding, HNPs bound to and promoted the binding of fibronectin to alpha5beta1 integrin in arginine-glycine-aspartic acid (RGD)-independent manner. HNPs also completely inhibited VEGF-induced proliferation and induced apoptosis of endothelial cells in a dose-dependent manner. Moreover, HNPs inhibited capillary tube formation in three-dimensional fibrin-matrices as well as neovascularization in vivo in the chicken chorioallantoic membrane assay. Taken together, these data indicate that HNPs can regulate angiogenesis by affecting endothelial cell adhesion and migration in an FN-dependent manner as well as endothelial cell proliferation. These findings provide new insight into the role of inflammatory cells in angiogenesis and might provide a platform for developing a novel class of anti-angiogenesis drugs.
Chavakis
Triantafyllos
T
Institute for Biochemistry, Justus-Liebig-Universität, Giessen, Germany. triantafyllos.chavakis@med.uni-heidelberg.de
Cines
Douglas B
DB
Rhee
Joong-Sup
JS
Liang
Olin D
OD
Schubert
Uwe
U
Hammes
Hans-Peter
HP
Higazi
Abd Al-Roof
AA
Nawroth
Peter P
PP
Preissner
Klaus T
KT
Bdeir
Khalil
K
D000818:Animals; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects; D002633:Chemotaxis / Q000187:drug effects; D049033:Chorioallantoic Membrane / Q000098:blood supply*; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D017270:Lipoprotein(a) / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011485:Protein Binding / Q000187:drug effects; D012160:Retina / Q000166:cytology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology; D023084:alpha-Defensins / Q000494:pharmacology* / Q000502:physiology
D005353:Fibronectins; D039081:Integrin alpha5beta1; D017270:Lipoprotein(a); D008246:Lysophospholipids; D042461:Vascular Endothelial Growth Factor A; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; C406427:human neutrophil peptide 3; C060506:sphingosine 1-phosphate; D013110:Sphingosine