Programmed Vascular Regression
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| The three temporary capillary networks of the neonatal eye |
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| Scanning electron micrographs showing the capillaries of the pupillary membrane extending from the iris diaphragm (ID) onto the anterior surface of the lens. The inset shows, at higher magnification, a macrophages close to a capillary. |
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| Image showing triple labeling for nuclei (blue), VE-Cadherin (a marker for endothelial cells) and alpha-smooth muscle actin (a marker for pericytes) in capillaries of the pupillary membrane. |
An ability to control vascular growth (angiogenesis) and regression would be invaluable in treating a variety of diseases. For this reason, and because of general interest in eye development, members of the Lang Lab at Cincinnati Children's Research Foundation have used the temporary capillary networks of the eye as model systems in which to study the mechanism of vascular regression.
In one avenue of investigation, we have shown that the activity of resident macrophages is required for the endothelial cell death that drives capillary regression (Lang and Bishop, 1993; Diez-Roux and Lang, 1997). This was considered a surprising result given that the major function of macrophages during development was traditionally thought to be scavenging debris from dying cells. Very recently, analysis in the worm C.elegans has shown that genes formerly thought to be involved only in dead cell recognition also have a role in promoting cell death (Hoeppner et al., 2001, Reddien et al, 2001). This activity is analogous to that we describe for macrophages in the eye and implies that phagocyte-induced programmed cell death is evolutionarily conserved.
Recently, we have been investigating the signaling pathways required for macrophage-induced capillary regression. Interestingly, mice that are mutated in the gene for Lrp5, a trans-membrane molecule and a putative Wnt co-receptor, have a completely persistent hyaloid vessel system (Kato et al., 2002). This may imply that Wnt signaling is required for macrophage killing activity or alternatively, that Lrp5 has a function unrelated to Wnt ligand signal transduction. Regardless, the Lrp5 mutant mice offer an excellent opportunity to understand the macrophage-endothelial cell interaction required for programmed capillary regression.
Another family of molecules implicated in regulation of programmed capillary regression are the Angiopoietins. These bind to and signal through the Tie2 receptor, a conventional tyrosine kinase. Angopietin 1 (Ang1) is an agonist of Tie2 signaling while Ang2, according to culture assays, is an antagonist. This has led to the suggestion that Ang2 might mediate capillary regression. We have tested this possibility in vivo by exposing the pupillary membrane to Ang2 via trans-corneal injections. This has shown that, at low levels of vascular endothelial growth factor (another endothelial-specific growth factor) Ang2 can induce endothelial cell death and capillary regression (Lobov et al, 2002). We are currently investigating whether there might be an endogenous source of Ang2 required for developmentally programmed regression.
How to Reach Us
The Lang Laboratory is part of the Division of Developmental Biology at Cincinnati Children's Research Foundation. The lab is located in Location R (Research Foundation Building), Room 1447.
Related Publications
Where possible, article titles are linked to an abstract of the article. Selected citations may also be linked to PDFs of the article available on a Journal's site. Depending on the Journal's publishing policy, you may need a subscription to download the PDF.
R.A. Lang and J.M. Bishop (1993). Macrophages are required for cell death and tissue remodeling during development of the mouse eye. Cell, 74, 453-462.
R.A. Lang, M. Lustig, F. Francois, M. Sellinger, and H. Plesken (1994). Apoptosis during macrophage- dependent ocular tissue remodelling. Development, 120, 3395-3404.
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A. Meeson, M. Calfon, M. Palmer and R. Lang (1996). A relationship between apoptosis and flow during programmed capillary regression is revealed by vital analysis. Development, 122, 3929-3938.
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A.O. Aliprantis, G. Diez Roux, L. Mulder, A. Zychlinsky and R.A. Lang (1996). Do macrophages kill through apoptosis? (review) Immunology Today, 17, 573-576.
R.A. Lang (1997). Apoptosis in mammalian eye development: lens morphogenesis, vascular regression and immune privilege (review). Cell Death and Differentiation, 4, 12-20.
G. Diez-Roux and R.A. Lang. (1997). Macrophages induce apoptosis in normal cells in vivo. Development, 124, 3633-3638.
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A. Meeson, M. Argilla, L. Witte, and R.A. Lang. (1999). VEGF deprivation-induced apoptosis is a component of programmed capillary regression. Development, 126, 1407-1415.
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G. Diez-Roux, M. Argilla, Kyung Ko and R.A. Lang (1999). Macrophages kill capillary cells in G1 phase of the cell-cycle during programmed vascular regression. Development, 126, 2141-2147.
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M. Kato, M.S. Patel, R. Levasseur, I. Lobov, B. Chang, D.A. Glass, II, C. Hartmann, L. Li, T.-H. Huang, C. Brayton, R.A. Lang, G. Karsenty, L. Chan. (2002). Abnormal osteoblast proliferation, low bone mass and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor. J. Cell Biology, 157, 303-314.
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I.B. Lobov, P. Brooks and R.A. Lang (2002). Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. PNAS, 99, 11205-11210.
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