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Blood, 1 February 2001, Vol. 97, No. 3, pp. 652-659
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
CD13/APN is activated by angiogenic signals and is
essential for capillary tube formation
Shripad V. Bhagwat,
Johanna Lahdenranta,
Ricardo Giordano,
Wadih Arap,
Renata Pasqualini, and
Linda H. Shapiro
From the Department of Pathology, St Jude Children's
Research Hospital, Memphis, TN, and Department of Medicine, MD
Anderson Research Hospital, Houston, TX.
In the hematopoietic compartment, the CD13/APN metalloprotease is
one of the earliest markers of cells committed to the myeloid lineage
where it is expressed exclusively on the surface of myeloid progenitors
and their differentiated progeny. CD13/APN is also found in
nonhematopoietic tissues, and its novel expression on the
endothelial cells of angiogenic, but not normal, vasculature was
recently described. Treatment of animals with CD13/APN
inhibitors significantly impaired retinal neovascularization,
chorioallantoic membrane angiogenesis, and xenograft tumor growth,
indicating that CD13/APN plays an important functional role in
vasculogenesis and identifying it as a critical regulator of
angiogenesis. To investigate the mechanisms of CD13/APN
induction in tumor vasculature, the regulation of
CD13/APN by factors contributing to angiogenic progression was studied. In this report, it is shown that
endogenous CD13/APN levels in primary cells and cell lines are
up-regulated in response to hypoxia, angiogenic growth factors, and
signals regulating capillary tube formation during angiogenesis.
Transcription of reporter plasmids containing CD13/APN
proximal promoter sequences is significantly increased in response to
the same angiogenic signals that regulate the expression of the
endogenous gene and in human tumor xenografts, indicating that this
fragment contains elements essential for the angiogenic induction of
CD13/APN expression. Finally, functional antagonists of
CD13/APN interfere with tube formation but not proliferation of primary
vascular endothelial cells, suggesting that CD13/APN functions in
the control of endothelial cell morphogenesis. These studies
clearly establish the CD13/APN metalloprotease as an important
regulator of endothelial morphogenesis during angiogenesis.
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