SELECTIVE BINDING OF PLATELET FACTOR-4 TO REGIONS OF ACTIVE ANGIOGENESIS IN-VIVO

In a previous study we suggested that recombinant human platelet facto r 4 (rhPF4) preferentially binds in vivo to regions of active angiogen esis/endothelial cell migration. To test this hypothesis, binding of f luorescently labeled rhPF4 to newly formed vessels was compared with t hat of the normal skin vasculature, using syngeneic Langerhans islets as inducers of angiogenesis. Islets were implanted in the dorsal skinf old chamber of the hamster, and the binding of rhPF4 was studied using intravital fluorescence microscopy. Intra-arterially injected rhPF4 l abeled, with high intensity, the endothelium along newly formed vessel s of the islets (1,632 +/- 617 mu m labeled vessel length per islet), and only on rare occasions (1 +/- 2 sites per cm(2) skinfold) were sho rt (62 +/- 48 mu m) intense-labeled sites found in the normal vasculat ure of the skinfold. Heparin could displace most of the label if injec ted within 10 min after the rhPF4 injection, but not 30 min after. In conclusion, rhPF4-preferentially binds to regions of active angiogenes is in vivo. On binding, rhPF4 is internalized as judged from a decreas ing heparin sensitivity with time after rhPF4 injection. The infrequen t rhPF4-labeling sites in the normal skin vasculature most likely repr esent regions of newly formed cells/migration, i.e., normal endothelia l turnover, supporting our previous findings demonstrating that the oc currence of such regions is rare in the normal microvasculature. Furth ermore, despite the previously demonstrated short half-life in plasma, systemically injected rhPF4 will target regions of angiogenesis with high affinity, thereby facilitating the antiangiogenic effect of PF4.