Cell cycle–dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity
Paola Romagnani, Francesco Annunziato, Laura Lasagni, Elena Lazzeri, Chiara Beltrame, Michela Francalanci, Mariagrazia Uguccioni, Grazia Galli, Lorenzo Cosmi, Lucia Maurenzig, Marco Baggiolini, Enrico Maggi, Sergio Romagnani, Mario Serio
Paola Romagnani, Francesco Annunziato, Laura Lasagni, Elena Lazzeri, Chiara Beltrame, Michela Francalanci, Mariagrazia Uguccioni, Grazia Galli, Lorenzo Cosmi, Lucia Maurenzig, Marco Baggiolini, Enrico Maggi, Sergio Romagnani, Mario Serio
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Cell cycle–dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity

Abstract

Endothelial cell receptors for the angiostatic chemokines IFN-γ–inducible protein of 10 kDa (IP-10) and monokine induced by IFN-γ (Mig) have not yet been identified, and the mechanisms responsible for the effects of these chemokines on angiogenesis are still unclear. IP-10 and Mig share a common functional receptor on activated T lymphocytes, named CXC chemokine receptor 3 (CXCR3). Using in situ hybridization and immunohistochemistry, we show that CXCR3 is expressed by a small percentage of microvascular endothelial cells in several human normal and pathological tissues. Primary cultures of human microvascular endothelial cells (HMVECs) likewise express CXCR3, although this expression is limited to the S/G2-M phase of their cell cycle. Both IP-10 and Mig, as well as the IFN-γ–inducible T-cell α chemoattractant (I-TAC), which all share high-affinity binding for CXCR3, block HMVEC proliferation in vitro, an effect that can be inhibited by an anti-CXCR3 antibody. These data provide definitive evidence of CXCR3 expression by HMVEC and open new avenues for therapeutic interventions in all conditions in which an angiostatic effect may be beneficial.

Authors

Paola Romagnani, Francesco Annunziato, Laura Lasagni, Elena Lazzeri, Chiara Beltrame, Michela Francalanci, Mariagrazia Uguccioni, Grazia Galli, Lorenzo Cosmi, Lucia Maurenzig, Marco Baggiolini, Enrico Maggi, Sergio Romagnani, Mario Serio

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Figure 6

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Association between CXCR3 and cyclin expression in HMVECs, but not in HM...
Association between CXCR3 and cyclin expression in HMVECs, but not in HMCs. HMVECs were synchronized in the G0–G1 phase of their cell cycle by contact inhibition and withdrawal of essential growth factors and then assessed for both CXCR3 and cyclin A expression (a, left). Parallel cell cultures that were not yet confluent were stimulated for 48 hours with bFGF and also assessed for CXCR3 and cyclin A (a, middle) or cyclin B1 (a, right) expression. HMCs stimulated under the same experimental conditions were also assessed at the same time for both CXCR3 and cyclin A expression (b). One representative of three separate experiments is shown.