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First published online 22 July 2003
doi: 10.1242/jcs.00629
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Research Article |
1 Department of Pathology, University of Washington, Seattle, WA 98195,
USA
2 IFOM, Institute FIRC for Molecular Oncology, Milan 20139, Italy
3 Department of Engineered Biomaterials, University of Washington, Seattle, WA
98195, USA
4 Veterans Administration Puget Sound Health Care System, Seattle, WA 98108,
USA
* Author for correspondence (e-mail: roberto.nicosia{at}med.va.gov)
Accepted 22 April 2003
Recent studies have implicated the Tie2 tyrosine-kinase receptor and its
main ligands - angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) - as crucial
regulators of mural cell recruitment during angiogenesis.
Angiopoietin-mediated activation of Tie2 promotes perivascular mural cell
assembly, but the mechanisms regulating this process are poorly understood
because differentiated mural cells do not have the Tie2 receptor, which is
reportedly expressed only in endothelial cells. There is also no direct
evidence that Tie2 activation results in production of mural cell
chemoattractants by the endothelium. In the rat aorta model of angiogenesis,
developing microvessels recruit mural cells from the intimal/subintimal layers
of the aortic wall. Ang-1 and Ang-2 promote angiogenesis in this system,
stimulating branching morphogenesis and mural cell assembly. Mural precursor
cells (MPCs) isolated with a nonenzymatic method from the intimal aspect of
the rat aorta were positive for smooth muscle cell markers (
-smooth
muscle actin and calponin) and negative for endothelial markers
(factor-VIII-related antigen and CD31). These cells responded chemotactically
to Ang-1 and Ang-2, and secreted MMP-2 when treated with these factors.
Western-blot analysis, immunocytochemistry and RT-PCR demonstrated that MPCs
express the Tie2 receptor. Immunoprecipitation showed phosphorylation of MPC
Tie2 on tyrosine residues upon stimulation with Ang-1 or Ang-2. Surface
expression of Tie2 was further demonstrated by isolating
Tie2+/-smooth muscle actin+ MPCs from primary
aortic outgrowths with anti-Tie2-IgG-coated magnetic beads. Immunostaining of
the rat aorta confirmed expression of Tie2 not only in endothelial cells but
also in nonendothelial mesenchymal cells located in the aortic
intimal/subintimal layers, which are the source of MPCs. These data indicate
that the aortic wall contains Tie2+ nonendothelial mesenchymal
cells and suggest that Tie2-related recruitment of mural cells during
angiogenesis may occur through angiopoietin-mediated direct stimulation of
these cells.
Key words: Angiogenesis, Angiopoietins, Tie2, Mural cells, Pericytes
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