Chemokines and angiostasis

Chemokines were originally defined by, and are still best known for, their ability to activate the motility of leukocytes. Still, certain other cell types can bind these factors, and there are hints that chemokines can regulate other cellular functions. In particular, various members of the CXC family of chemokines can activate or suppress angiogenesis through signaling pathways that are not yet well described. Romagnani et al. report here that human microvascular endothelial cells from a variety of normal tissues express the chemokine receptor CXCR3, several of whose ligands are strongly angiostatic. Interestingly, cultured endothelial cells are heterogeneous with respect to CXCR3 expression. The authors show that these cells fail to express the CXCR3 mRNA while they remain in the G0 or G1 phases of the cell cycle, but that the receptor is induced in parallel with the cell cycle regulator cyclin A. In vivo, the proportion of CXCR3-positive cells is generally low and increases during inflammation, when the normally quiescent endothelial cells enter the cell cycle. This cell cycle dependence is not seen in other cell types that express the CXCR3 receptor. Because endothelial cells induce receptor expression in this manner, they become sensitive to the antiproliferative effect of specific chemokines precisely when they are dividing or preparing to divide. Presumably, this pathway provides an additional mechanism for the physiological control of angiogenesis, one that might be exploited to block tumor angiogenesis.