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Prepublished online as a Blood First Edition Paper on September 4, 2003; DOI 10.1182/blood-2003-05-1387.
Submitted May 2, 2003
Accepted August 21, 2003
CCL16 activates an angiogenic program in vascular endothelial cells
Marina Strasly, Gabriella Doronzo, Paola Capello, Donatella Valdembri, Marco Arese, Stefania Mitola, Paul Moore, Giulio Alessandri, Mirella Giovarelli, and Federico Bussolino*
Institute of Cancer Research and Treatment, University of Turin, Turin, Italy; Department of Oncological Sciences, University of Turin, Turin, Italy
Department of Clinical and Biological Sciences, University of Turin, Turin, Italy; Center for Experimental Research and Medical Studies, S. Giovanni Battista Hospital, Turin, Italy
Department of Cell Biology and Molecular Biology, Human Genome Sciences Inc., Rockvillle, MD, USA
Laboratory of Neurobiology and Neurorigenerative Therapy, Institute C. Besta, Milan, Italy
* Corresponding author; email: federico.bussolino{at}ircc.it.
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 in a dose-dependent way random and directional migration of endothelial cells isolated from large vessels and liver capillaries without inducing their proliferation. It promotes endothelial differentiation into capillary-like structure in an in vitro assay and is angiogenic in 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, two other angiogenic chemokines. BX471, a CCR1 antagonist, inhibits angiogenic properties of CCL16, while blocking of CCR8 or desensitising 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.
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