METHODS: The effects of rBPI(21) and
XMP.Z on
VEGF-induced growth of bovine
retinal microvascular endothelial cells (BRECs) and on serum-induced growth of bovine
retinal pericytes (BRPs) and
retinal pigment epithelial cells (BRPECs) were evaluated by determining total
DNA content. The neonatal mouse model of
retinopathy of prematurity (ROP) was used to study the effect of
XMP.Z in vivo.
Intraperitoneal injections of the
peptidomimetic (10 mg/kg) were administered every 24 hours for 5 days (postnatal [P]12-P17) during induction of neovascularization.
Retinal neovascularization was evaluated using flatmounts of
fluorescein-dextran-perfused retinas and quantitated by counting
retinal cell nuclei anterior to the internal limiting membrane. RESULTS.
VEGF (25 ng/mL) increased the total
DNA per well of BRECs by 120% +/- 50% (P < 0.001), which was inhibited by addition of rBPI(21) or
XMP.Z, with decreases of 77% +/- 15% (P < 0.05) and 107% +/- 19% (P < 0.01) at maximum effective doses of 75 and 15 microg/mL rBPI(21) and
XMP.Z, respectively. In contrast, rBPI(21) at 75 microg/mL enhanced the total
DNA per well of BRP 53% +/- 14% (P < 0.001) in the presence of 5%
fetal bovine serum (FBS), whereas
XMP.Z enhanced BRP growth by 27% +/- 7% (P < 0.001) at 5 microg/mL. In the presence of 10% FBS, rBPI(21) and
XMP.Z increased BRP growth by 91% +/- 35% (P < 0.001) and 43% +/- 18% (P < 0.01), respectively. In the
oxygen-induced ROP neonatal mouse model,
retinal neovascularization was decreased by 40% +/- 16% (n = 5, P < 0.01) when animals were treated with
XMP.Z.
CONCLUSIONS: Two BPI-derived compounds, rBPI(21) and
XMP.Z, significantly suppressed
VEGF-induced BREC growth in vitro, while conversely enhancing the growth of BRPs, even above that induced by 20% FBS. When tested in animals,
XMP.Z also suppressed
ischemia-induced
retinal neovascularization in mice. These data suggest that BPI-derived compounds may have unique therapeutic potential for proliferative
retinal diseases such as
diabetic retinopathy, if physiological levels can be achieved in clinical settings.