Rb. Vernon et Eh. Sage, A novel, quantitative model for study of endothelial cell migration and sprout formation within three-dimensional collagen matrices, MICROVASC R, 57(2), 1999, pp. 118-133
Interactions between migratory endothelial cells (ECs) and surrounding extr
acellular matrix (ECM) are of central importance to vascular growth. Here,
we present a new model of EC migration and morphogenesis within three-dimen
sional ECM termed "radial invasion of matrix by aggregated cells" (RIMAC).
In the RIMAC model, single aggregates of defined numbers of bovine aortic E
Cs were embedded within small, lenticular gels of type I collagen supported
by annuli of nylon mesh. Culture of the gels in nutrient media resulted in
quantifiable, reproducible, radial migration of ECs into the collagen. The
angiogenic proteins basic fibroblast growth factor (bFGF) and vascular end
othelial growth factor (VEGF) each stimulated migration of ECs in a concent
ration-dependent manner. In combination, bFGF and VEGF stimulated migration
synergistically. In contrast, transforming growth factor-beta 1 inhibited
migration of ECs. Low concentrations (0.1-0.5 ng/ml) of VEGF induced ECs to
form multicellular sprouts, some of which possessed lumen-like spaces. Mit
omycin C, an inhibitor of cell proliferation, did not affect the migration
of ECs into collagen induced by 0.5 ng/ml VEGF but moderately inhibited mig
ration induced by 5 ng/ml VEGF. Increasing the density (concentration) of t
he collagen gel inhibited the migration of single ECs and increased the bra
nching and anastomosis of multicellular sprouts. We conclude that the RIMAC
model is a highly efficacious assay for the screening of potentially angio
genic and angiostatic compounds and, moreover, is advantageous for mechanis
tic studies of vascular morphogenesis. (C) 1999 Academic Press.