| Vascular endothelial growth factor (VEGF) mediates angiogenesis by promoting endothelial cell recruitment and proliferation, while Angiopoietin-1 (Ang-1) is suggested to have a role in vessel stability and perivascular cell recruitment. This study examines architectural changes in subcutaneous microvascular networks (including arterioles, capillaries, and venules) induced by temporally- and spatially-controlled applications of exogenous VEGF and Ang-1, and employs a novel cellular automata model to examine the integrated molecular and cellular behaviors contributing to microvascular remodeling.; The delivery and diffusion of I125-VEGF164 from 100 μm diameter alginate beads was characterized. Dorsal skin backpack window chambers were implanted into forty anesthetized 250–300 gram male Fisher 344 rats. Five days later, two beads containing 10 μg/ml VEGF (+PBS) and two containing vehicle control (PBS) were inserted into opposing tissue window quadrants. Bead delivery of VEGF164 caused a significant increase (p < 0.05) ± SD in the number of vessels with diameters less than 25 μm on Days 7 and 14 (78 ± 8%, and 80 ± 7% of total vessels) and their functional length density (499 mm/mm3 ± 42 and 512 ± 66 mm/mm3) compared to control (66 ± 5%, and 63 ± 4% of total vessels; 239 ± 34 mm/mm 3 and 255 ± 39 mm/mm3), but these levels were reduced to control levels by Day 21. A second dose of VEGF164 (73 ± 11% of total vessels; 416 ± 70 mm/mm3) and Ang-1 (76 ± 10% of total vessels; 458 ± 61 mm/mm3) at Day 7 caused increased diameter distributions and functional length density of vessels with diameters less than 25 μm out to day 21 compared to control (58 ± 8% of total vessels; 257 ± 59 mm/mm3).; These data suggest that local stimulation by exogenous VEGF164 produces an altered network morphology with an increased proportion of small vessels that persists for up to 14 days but is later pared down. The administration of Ang-1 after VEGF164 stimulation significantly increased the percentage of vessels with diameters less than 25 μm at Day 21, and the network structure was statistically similar to those networks stimulated by vehicle control. The amount of perivascular cell recruitment (88 ± 11%) was significantly increased at Day 14, above control levels (65 ± 14%). Therefore, we suggest that in this double-dose model VEGF164 stimulates the growth of new capillaries and Ang-1 stabilizes the new vessels by perivascular cell recruitment. (Abstract shortened by UMI.)... |
