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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-05-1422.
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Blood, 1 March 2003, Vol. 101, No. 5, pp. 1818-1826
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
The angiogenic regulator CD13/APN is a transcriptional target of
Ras signaling pathways in endothelial morphogenesis
Shripad V. Bhagwat,
Nenad Petrovic,
Yasuhiro Okamoto, and
Linda H. Shapiro
From the Departments of Pathology, and
Hematology/Oncology, St Jude Children's Research Hospital, Memphis,
TN; and the Center for Vascular Biology, Department of Physiology,
University of Connecticut Health Center, Farmington, CT.
Angiogenesis, the formation of new blood vessels, is a critical
step for tumor growth and metastasis and an integral component of the
pathologic inflammatory response in arthritis and the proliferative retinopathies. The CD13/aminopeptidase N (CD13/APN)
metalloprotease is an important regulator of angiogenesis where its
expression on activated blood vessels is induced by angiogenic signals.
Here, we show that cytokine induction of CD13/APN in
endothelial cells is regulated by distinct Ras effector pathways
involving Ras/mitogen-activated protein kinase (MAPK)
or PI-3K. Signals transduced by activated Ras, Raf, and mitogen-induced
extracellular kinase (MEK) stimulate transcription from the
CD13/APN proximal promoter. Inhibition of these
pathways and extracellular signal-regulated serine/threonine kinase
(ERK-2) and PI-3K by expression of dominant-negative proteins or chemical inhibitors prevented induction of CD13/APN
transcription in response to basic fibroblast growth
factor (bFGF). We show that Ras-induced signal
transduction is required for growth factor-induced angiogenesis,
because inhibition of downstream mediators of Ras signaling (MEK or
PI-3K) abrogated endothelial cell migration, invasion, and
morphogenesis in vitro. Reintroduction of CD13/APN, a shared downstream
target of these pathways, overrode the suppressive effect of these
inhibitors and restored the function of endothelial cells in
migration/invasion and capillary morphogenesis assays. Similarly,
inhibition of MEK abrogated cell invasion and the formation of
endothelial-lined capillaries in vivo, which was effectively rescued by
addition of exogenous CD13/APN protein. These studies provide strong
evidence that CD13/APN is an important target of Ras signaling in
angiogenesis and is a limiting factor in angiogenic progression.
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