Angiopoietin-1 induces endothelial cell sprouting through the activation of focal adhesion kinase and plasmin secretion.
Angiopoietin-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 p125(FAK), 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 alpha(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.
Kim
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I
National Creative Research Initiatives Center for Cardiac Regeneration,Institute of Cardiovascular Research, Department of Ophthalmology, Woosuk University, Chonju, Korea.
Kim
H G
HG
Moon
S O
SO
Chae
S W
SW
So
J N
JN
Koh
K N
KN
Ahn
B C
BC
Koh
G Y
GY
D042683:Angiopoietin-1; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects*; D004789:Enzyme Activation / Q000502:physiology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005341:Fibrinolysin / Q000378:metabolism*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D051419:Paxillin; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D011651:Pulmonary Artery / Q000166:cytology / Q000187:drug effects; D042787:Receptor, TIE-2; D013552:Swine; D014443:Tyrosine / Q000378:metabolism
D042683:Angiopoietin-1; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; C105373:MEN1 protein, human; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C496061:PXN protein, human; D051419:Paxillin; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D042787:Receptor, TIE-2; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D005341:Fibrinolysin; D020782:Matrix Metalloproteinases