Cellular Biology |
From the National Creative Research Initiatives Center for Cardiac Regeneration and Institute of Cardiovascular Research (I.K., H.G.K., S.-O.M., S.W.C., J.-N.S., K.N.K., G.Y.K.) and Department of Ophthalmology (B.C.A.), Chonbuk National University School of Medicine, and Department of Biotechnology (J.-N.S.), Woosuk University, Chonju, Korea.
Correspondence to Gou Young Koh, MD, PhD, National Creative Research Initiatives Center for Cardiac Regeneration, Chonbuk National University School of Medicine, San 2-20, Keum-Am-Dong, Chonju, 560-180, Republic of Korea. E-mail gykoh{at}moak.chonbuk.ac.kr
AbstractAngiopoietin-1 (Ang1) is
a strong inducer of endothelial cell sprouting, which
is a first step in both angiogenesis and neovascularization. We
examined the mechanisms underlying Ang1-induced cell sprouting using
porcine pulmonary artery endothelial cells.
Ang1 induced the nondirectional and directional migration of
endothelial cells mediated through the Tie2 but not the
Tie1 receptor. Ang1 induced tyrosine phosphorylation of
p125FAK, and this phosphorylation was
dependent on phosphatidylinositol (PI) 3'-kinase activity. Ang1 induced
the secretion of plasmin and matrix metalloproteinase-2 (MMP-2), which
is inhibited by PI 3'-kinase inhibitors. Ang1 also induced
the secretion of small amounts of proMMP-3 and proMMP-9 but not
proMMP-1. Ang1 suppressed the secretion of tissue inhibitor
of metalloproteinase-2 (TIMP-2), but not of TIMP-1. Addition of
2-antiplasmin, a combination of TIMP-1 and TIMP-2, or PI
3'-kinase inhibitors inhibited Ang1-induced sprouting
activity. Therefore, Ang1-induced sprouting activity in
endothelial cells may be accomplished by cytoskeletal
changes and secretion of proteinases and may be largely mediated
through intracellular PI 3'-kinase activation.
Key Words: angiopoietin-1 sprouting p125FAK plasmin
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