© 2000 American Heart Association, Inc.
Cellular Biology |
1
,25-Dihydroxyvitamin D3 Inhibits Angiogenesis In Vitro and In Vivo
From the Wellcome Trust Centre for Cell Matrix Research, Department of Medicine (D.J.M., P.E.O., E.B.M., A.E.C.) and Surgery (N.J.B.), University of Manchester, Manchester, UK.
Abstract—Modulation of
angiogenesis is now a recognized strategy for the prevention and
treatment of pathologies categorized by their reliance on a vascular
supply. The purpose of this study was to evaluate the effect of
1
,25-dihydroxyvitamin D3
[1,25(OH)2D3], the active metabolite of
vitamin D3, on angiogenesis by using well-characterized in
vitro and in vivo model systems. 1,25(OH)2D3
(1x10-9 to 1x10-7
mol/L) significantly inhibited vascular endothelial
growth factor (VEGF)-induced endothelial cell sprouting
and elongation in vitro in a dose-dependent manner and had a small, but
significant, inhibitory effect on VEGF-induced
endothelial cell proliferation.
1,25(OH)2D3 also inhibited the formation of
networks of elongated endothelial cells within 3D
collagen gels. The addition of 1,25(OH)2D3 to
endothelial cell cultures containing sprouting
elongated cells induced the regression of these cells, in the absence
of any effect on cells present in the cobblestone monolayer.
Analysis of nuclear morphology, DNA integrity, and enzymatic in
situ labeling of apoptosis-induced strand breaks demonstrated
that this regression was due to the induction of apoptosis
specifically within the sprouting cell population. The effect of
1,25(OH)2D3 on angiogenesis in vivo was
investigated by using a model in which MCF-7 breast carcinoma cells,
which had been induced to overexpress VEGF, were xenografted
subcutaneously together with MDA-435S breast carcinoma cells into nude
mice. Treatment with 1,25(OH)2D3 (12.5 pmol/d
for 8 weeks) produced tumors that were less well vascularized than
tumors formed in mice treated with vehicle alone. These results
highlight the potential use of 1,25(OH)2D3 in
both the prevention and regression of conditions characterized by
pathological angiogenesis.
Key Words: endothelium • angiogenesis • apoptosis • vitamin D3 • growth factors
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