From the Departments of Medicine (Cardiology) and Biomedical Research, St
Elizabeth's Medical Center, Tufts University School of Medicine, Boston,
Mass (E.V.B., B.W., D.C., M.S., J.M.I.) and Genentech Inc, South San
Francisco, Calif (L.C., R.S.).
Correspondence to Jeffrey M. Isner, MD, St Elizabeth's Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail jisner{at}opal.tufts.edu
Background—Scatter
factor/hepatocyte growth factor (SF/HGF) is a pleiotropic
growth factor that stimulates proliferation and migration of
endothelial cells (ECs) via the c-Met
receptor, present on ECs as well as other cell types, including
smooth muscle cells (SMCs). We studied the effects of recombinant human
(rh) SF/HGF in vitro and in vivo in a rabbit model of hindlimb
ischemia. We further compared these effects with those of
recombinant human vascular endothelial growth factor
(rhVEGF165), an EC–specific mitogen.
Methods and Results—In vitro, rhSF/HGF and rhVEGF165
exhibited similar effects on proliferation and migration of ECs. When
both cytokines were administered together, the result was an
additive effect on EC proliferation and a synergistic effect on EC
migration. Application of rhSF/HGF to cultures of human SMCs resulted
in the induction of VEGF mRNA and protein. In vivo, administration of
rhSF/HGF (500 µgx3) was associated with significant improvements in
collateral formation (P<.001) and regional blood flow
(P<.0005) and with a significant reduction in muscle
atrophy (P<.0001). These effects were significantly
more pronounced than those of rhVEGF165 administered
according to the same protocol (P<.05). Neither remote
angiogenesis nor other pathological sequelae were observed with either
rhSF/HGF or rhVEGF165.
Conclusions—The pleiotropic effects of certain growth factors may
potentiate angiogenesis via a combination of direct effects on EC
proliferation and migration and indirect effects that result in the
generation of other potent EC mitogens from non-EC populations. The
synergistic effects demonstrated when SF/HGF and VEGF are administered
together in vitro may be reproduced in vivo by SF/HGF-induced
upregulation of VEGF in vascular SMCs.
© 1998 American Heart Association, Inc.
Basic Science Reports
Potentiated Angiogenic Effect of Scatter Factor/Hepatocyte Growth Factor via Induction of Vascular Endothelial Growth Factor
The Case for Paracrine Amplification of Angiogenesis
Key Words: growth substances • angiogenesis • collateral circulation • endothelium
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