INTERLEUKIN-8 AND DE-NOVO MAMMALIAN ANGIOGENESIS

In the rat mesenteric-window angiogenesis assay (MWAA), the test tissu e is natively vascularized, lacks significant physiological angiogenes is and its homeostasis is unperturbed by surgical intervention. Using the rat MWAA, it is shown here that interleukin-8 (IL-8), administered at approximately physiological doses, is able to induce de novo angio genesis. Human recombinant IL-8 was administered intraperitoneally at two daily doses of 25 pM, 250 pM and 2.5 nM for 5 consecutive days (da ys 0-4). Using microscopic, computer-aided techniques including image analysis, the de novo angiogenic response was quantified in groups of animals on days 7, 14 and 21 in terms of the relative vascularized are a (VA), a measure of the microvascular spatial extension, and the micr ovascular length (MVL), a measure of microvascular density or length. The total microvascular length (TMVL) was computed from VA x MVL. A st atistically significant angiogenic effect was found in terms of MVL on day 7 and in terms of VA and TMVL on day 14 following the treatment w ith 2.5 nM, whereas MVL was significantly increased in statistical ter ms on day 14 following the treatment with IL-8 at the low dose of 25 p M. Notably, IL-8 at the intermediate dose of 250 pM did not induce a s tatistically significant angiogenic effect in terms of VA, MVL or TMVL on any observation occasion, thereby suggesting that the dose-related angiogenic effect of IL-8 may be nonlinear. This appears to be the fi rst paper showing that IL-8 is able to induce de novo angiogenesis in normally vascularized mammalian tissue.