Differential regulation of pericyte function by the CXC receptor 3

Pericytes are mural cell that have been found to play important roles in promoting blood vessel development and regulating blood flow. The signals that attract pericytes to maturing vessels during the resolution phase of wound healing are unknown. In this study, we examine the role of the chemokine receptor CXC receptor 3 (CXCR3) ligands, as they are produced by maturing endothelial cells. Pericytes isolated from muscle and retina were found to by and large only express the B-isoform of CXCR3 (CXCR3B), with expression being independent of the mitotic state of the cells. Pericyte stimulation with the CXCR3 ligands Mig (CXCL9), IP-9/I-TAC (CXCL11), or IP-10 (CXCL10) resulted in the activation of ERK but not AKT. Treatment with Mig or IP-9, but not IP-10, enhanced p38(MAPK) phosphorylation. Interestingly, while cyclic adenosine monophosphate is generated downstream of CXCR3B in other cells, protein kinase A activation was not observed in these pericytes when treated with these three CXCR3 ligands. The increase in ERK activity resulted in a slight increase in cell transmigration, with the inhibition of ERK leading to a decrease in CXCR3B mediated migration and inhibition of p38(MAPK) reducing transmigration through small pores. These ligands did not affect proliferation. These data are the first to characterize CXCR3B as the predominant isoform expressed on pericytes, and was found on these diverse cells isolated from both muscle and eye. We also show that CXCR3B signaling stimulates transmigration of barrier pores in pericytes as opposed to its inhibitory affects on endothelial cells and fibroblasts. These findings characterize a novel role for the CXCR3B in regulating cellular function. Taken together these data show a role for CXCR3B in regulating pericyte function.