To illustrate one pathway, Biancone et al. [
30] showed that the homing of EPCs involves the expression of L-selectin, an adhesion receptor on EPCs, and its ligand in ischemic sites. Chavakis et al. [
31] demonstrated in a murine model of hind-limb ischemia that preactivation of the beta-2 integrins expressed on EPCs via activating antibodies enhances the homing and neovascularization of EPCs
in vivo. Moreover, Duan et al. [
32] indicated that leukocyte function-associated antigen (LFA-1, alpha-L-beta-2, and CD11a/CD18) and integrin alpha-4-beta-1 (very late antigen-4, VLA-4) expressed in human umbilical cord blood-derived high proliferative potential-endothelial progenitor cells (HPP-EPCs) are involved in HPP-EPCs homing to ischemic tissues via the interaction with their ligands, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), expressed in vessel endothelium in ischemic tissues, which can be blocked by CD11a and CD49d antibodies. Lev et al. [
33] demonstrated that platelets play a role in the homing of EPCs to injury sites. The interaction between EPCs and activated platelets under static and flow conditions is mediated through P-selectin-P-selectin glycoprotein ligand-1 (PSGL-1) interaction
in vitro, which is inhibited by antibodies to P-selectin or PSGL-1, but not by antibodies to glycoproteins Ib-IX-V or IIb/IIIa. Additionally, Sbaa et al. [
34] reported that EPC transduction with caveolin small interfering RNA, which mediates the endocytosis of CXCR4, regulating both the SDF-1-mediated mobilization and peripheral homing of EPCs to ischemia sites, leads to a more extensive rescue of the ischemic hind-limb. Chavakis et al. [
35] showed that EPCs express high-mobility group protein B1 (HMGB1) receptors, including receptors for advanced glycation end products (RAGE) and toll-like receptor 2 (TLR2), but HMGB1 stimulates the migration of EPCs in a RAGE-dependent manner, where HMGB1 increases EPC adhesion to the immobilized integrin ligands, ICAM-1 and fibronectin. Besides, HMGB1 rapidly increases integrin affinity and induces integrin polarization. What is more, Maeng et al. [
20] reported that the remarkably promoting role of the IGF2/IGF2R system in EPC homing is mainly via IGF2R-linked G(i) protein signaling and intracellular calcium (Ca
2+) mobilization which is induced by the beta-2 isoform of phospholipase C. Zhao et al. [
36] thought that sphingomyelin synthase 2 (SMS2) over-expression is probably associated with an increase in expression of aortic inflammatory biomarkers, as well as a decrease in the number of CD34/KDR-positive cells, circulating angiogenic cells (CACs), and CFU in circulation in apolipoprotein E (ApoE) KO mice. What is more, Shen et al. [
37] indicated that the SDF-1alpha-small GTPaseRAC signaling pathway plays an important role in polarity, morphology variation, and the direction of migration of EPCs, which is induced by SDF-1alpha. Finally, Wang et al. [
38] showed that peroxisome proliferator-activated receptor (PPAR)-alpha restrains ischemia-induced EPC mobilization and homing via inhibition of the HIF-1alpha/SDF-1 pathway during retinal neovascularization. Furthermore, chemokine (C-C motif) ligand 5 (CCL5) induces
in vitro EPC homing in a C-C chemokine receptor type 5 (CCR5)-dependent manner. The CCL5/CCR5 interaction will be a novel molecular target for modulation of neovascularization and eventual tissue repair [
39]. EPCs can express C-X-C chemokine receptor type 2 (CXCR2), and damaged arterial smooth muscle cells (SMCs) up-regulate the expression of chemokine (C-X-C motif) ligand 7 (CXCL7) and CXCL1. The binding between CXCR2 and CXCL1 or CXCL7 can also enhance the homing of circulating EPCs to sites of arterial injury and endothelial recovery
in vivo [
40]. E-selectin not only stimulates ECs to express ICAM-1 but also EPCs to secrete IL-8, leading to enhanced homing and incorporation of EPCs to ECs capillary formation [
41]; the issue of whether this process occurs after ischemic stroke remains to be distinctly elucidated.