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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2000;20:1250.)
© 2000 American Heart Association, Inc.

Vascular Biology

Fibroblast Growth Factor-2 Selectively Stimulates Angiogenesis of Small Vessels in Arterial Tree

Patricia Parsons-Wingerter; Katherine E. Elliott; John I. Clark; Andrew G. Farr

From the Department of Biological Structure (P.P.-W., J.I.C., A.G.F.), University of Washington School of Medicine, Seattle, and the 3Com Corp (K.E.E.), Bellevue, Wash.

Correspondence to Patricia Parsons-Wingerter, PhD, Department of Anatomy and Cardiovascular Research Institute, University of California, San Francisco, 513 Parnassus Ave, San Francisco, CA 94143-0130.

Abstract—There is a critical need for quantifiable models of angiogenesis in vivo, and in general, differential effects of angiogenic regulators on vascular morphology have not been measured. Because the potent angiogenic stimulators fibroblast growth factor (FGF)-2 (basic FGF) and vascular endothelial growth factor (VEGF) are reported to stimulate angiogenesis through distinct signaling pathways, we hypothesized that FGF-2 stimulates vascular morphology differently than does VEGF and that stimulation of angiogenesis by FGF-2 is directly correlated to FGF receptor density. FGF-2 was applied at embryonic day 7 (E7), E8, or E9 to the quail chorioallantoic membrane (CAM); subsequent response of the arterial tree was measured by the fractal dimension (D_f), a mathematical descriptor of complex spatial patterns, and by several generational branching parameters that included vessel length density (L_v). After application of FGF-2 at E7, arterial density increased according to D_f as a direct function of increasing FGF-2 concentration, and FGF-2 stimulated the growth of small vessels, but not of large vessels, according to L_v and other branching parameters. For untreated control specimens at E7, L_v of small vessels and D_f were 11.1±1.6 cm^-1 and 1.38±0.01, respectively; at E8, after treatment with 5 µg FGF-2/CAM for 24 hours, L_v of small vessels and D_f increased respectively to 22.8±0.7 cm^-1 and 1.49±0.02 compared with 16.3±0.9 cm^-1 and 1.43±0.02 for PBS-treated control specimens. Application of FGF-2 at E8 and E9 did not significantly increase arterial density. By immunohistochemistry, the expression of 4 high-affinity tyrosine kinase FGF receptors was significantly expressed at E7, when CAM vasculature responded strongly to FGF-2 stimulation, but FGF receptor expression decreased throughout the CAM by E8, when vascular response to FGF-2 was negligible. In conclusion, the "fingerprint" vascular pattern elicited by FGF-2 was distinct from vascular patterns induced by other angiogenic regulators that included VEGF₁₆₅, transforming growth factor-ß1, and angiostatin.

Key Words: quail • chorioallantoic membrane • fractal dimension • fibroblast growth factor receptors • complexity

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