CCL16 activates an angiogenic program in vascular endothelial cells.
Besides regulating leukocyte trafficking in normal and injured tissues, several chemokines may positively or negatively regulate angiogenesis. Here we report that CCL16 activates an angiogenic program in vascular endothelial cells by activating CCR1. CCL16 induces dose-dependent random and directional migration of endothelial cells isolated from large vessels and liver capillaries without inducing their proliferation. It also promotes endothelial differentiation into capillary-like structures in an in vitro assay and is angiogenic in the chick chorionallantoic membrane. These angiogenic activities are neutralized by a specific antibody against CCL16. The direct angiogenic activity of CCL16 is further amplified by its ability to prime endothelium to a mitogen signal induced by vascular endothelial growth factor A and to raise their basal production of CXCL8 and CCL2, 2 other angiogenic chemokines. BX471 (R-N-[5-chloro-2-[2-[4(4-fluorophenyl) methyl]-2-methyl-1-piperazinyl]-2-oxoethoxy]phenyl] urea hydrochloric acid salt), a CCR1 antagonist, inhibits angiogenic properties of CCL16, whereas blocking of CCR8 or desensitizing CCR2, which are both well known receptors for CCL16, did not abolish endothelial activation. CCL16 may be specifically cross-linked to CCR1 expressed on endothelial cells. The largely restricted CCL16 expression in the liver suggests that this chemokine may play a role in hepatic vascular formation during development and in angiogenesis associated to hepatic diseases.
Strasly
Marina
M
Division of Molecular Angiogenesis, Institute for Cancer Research and Treatment (IRCC), University of Turin, School of Medicine, Candiolo, Italy.
Doronzo
Gabriella
G
Cappello
Paola
P
Capello
Paola
P
Valdembri
Donatella
D
Arese
Marco
M
Mitola
Stefania
S
Moore
Paul
P
Alessandri
Giulio
G
Giovarelli
Mirella
M
Bussolino
Federico
F
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D019742:Chemokines, CC / Q000494:pharmacology*; D019743:Chemokines, CXC / Q000378:metabolism; D002642:Chick Embryo; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development* / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008934:Mitogens / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
C481939:CCL16 protein, human; C515300:CCR1 protein, human; C515334:CCR2 protein, human; D019742:Chemokines, CC; D019743:Chemokines, CXC; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D054389:Receptors, CCR1; D054390:Receptors, CCR2; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A