© 2000 American Heart Association, Inc.
Vascular Biology |
Lysophosphatidylcholine Inhibits Endothelial Cell Migration and Proliferation via Inhibition of the Extracellular Signal–Regulated Kinase Pathway
From the First Department of Internal Medicine (Y.R., S.K., T.Y., T.U., K.H., M.Y.), and the Department of Microbiology (S.I., H.H.), Kobe University School of Medicine, Kobe, Japan.
Correspondence to Seinosuke Kawashima, MD, First Department of Internal Medicine, Kobe University School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. E-mail kawashim{at}med.kobe-u.ac.jp
Abstract—Lysophosphatidylcholine
(lysoPC), a major lipid component of oxidized low density lipoprotein,
inhibits endothelial cell (EC) migration and
proliferation, which are critical processes during angiogenesis and the
repair of injured vessels. However, the mechanism(s) of lysoPC-induced
inhibition of EC migration and proliferation has not been clarified. In
this report, we demonstrate the critical role of extracellular
signal–regulated kinase (ERK) in growth factor–stimulated EC
migration and proliferation as well as their inhibition by lysoPC. EC
migration and proliferation stimulated by basic fibroblast growth
factor (FGF-2) were blocked by inhibition of ERK activity by both the
specific mitogen-activated protein kinase kinase (MEK) 1
inhibitor PD98059 and the overexpression of a
dominant-negative mutant of MEK1. Conversely, overexpression of a
constitutively active mutant of MEK1 increased EC migration and
proliferation, which were comparable to those of ECs stimulated with
FGF-2. LysoPC inhibited FGF-2–induced ERK activation via prevention of
Ras activation without inhibiting tyrosine
phosphorylation of phospholipase C-
. Taken together,
our data demonstrate that ERK activity is required for FGF-2–induced
EC migration and proliferation and suggest that inhibition of the
Ras/ERK pathway by lysoPC contributes to the reduced EC migration
and proliferation.
Key Words: angiogenesis • lysophosphatidylcholine • signal transduction • basic fibroblast growth factor
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