Chemotaxis of human microvessel endothelial cells in response to acidic fibroblast growth factor.
Migration of microvessel endothelial cells (MEC) in response to angiogenic stimuli is a key aspect of angiogenesis, whether in physiologic or pathologic situations. In this work, we provide a rigorous quantitative assessment of the chemokinetic and chemotactic responses of human MEC to acidic fibroblast growth factor (aFGF). A uniform concentration of 1 micrograms/ml of heparin was included in most experiments to exploit heparin's potentiating effect on aFGF activity. The migration is measured in an under-agarose assay with a linear geometry, and evaluated in terms of the random motility and chemotaxis coefficients, mu and chi, which are defined in a mathematical model. The change in value of mu with changes in aFGF concentration provides a quantitative description of the stimulated random motility response, a process known as chemokinesis. This allows the true directional response in gradients to be quantified by the chemotaxis coefficient, chi, and its variation with attractant concentration. The effect of aFGF on MEC random motility is relatively small, with the random motility coefficient ranging from 4.6 +/- 0.4 x 10(-9) to 9.9 +/- 0.3 x 10(-9) cm2/second (mean +/- SE) over four orders of magnitude of aFGF concentration (10(-11) to 10(-8) M). On the other hand, the magnitude of the chemotaxis coefficient at optimal concentrations is quite large (2600 +/- 750 cm2/second-M around 10(-10) M aFGF), demonstrating a significant degree of MEC directional sensitivity to aFGF gradients. The chemotaxis coefficient shows a biphasic dependence on aFGF concentration, suggestive of a receptor-mediated response in which apparent differences in receptor occupancy govern directional bias. These results provide support for the hypothesis that MEC chemotaxis accounts for the directed microvessel growth observed in angiogenesis.
Department of Chemical Engineering, University of Pennsylvania, Philadelphia.
C L
CL
Stokes
M A
MA
Rupnick
S K
SK
Williams
D A
DA
Lauffenburger
D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D005346:Fibroblast Growth Factors / Q000494:pharmacology*; D008954:Models, Biological; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D014471:Umbilical Veins / Q000187:drug effects / Q000502:physiology
D005346:Fibroblast Growth Factors