Restoration of faulty blood vessel architecture by angiopoietin-1

December 03, 2002

Angiogenesis (the growth of new blood vessels) requires complex signaling between multiple cell types, and abnormalities in these pathways results in faulty vessels. During normal vessel formation endothelial cells that comprise the blood vessel communicate, through a number of secreted agents called growth factors, with a family of cells known as mural cells. Endothelial cells secrete the growth factor PDGF B that is bound to mural cells by the PDGF-b receptor. Murals cells are then recruited to the new vessel where upon direct interaction with endothelial cells they secrete angiopoietin-1 (Ang1). Multiple roles in vessel maturation have been designated to Ang1 and they include sprouting, survival and stability of the new vessel.

However, the exact nature of its involvement is unclear. The critical interactions between endothelial cells and mural cells facilitate the growth and maturation of new blood vessels. In diseases such as diabetic retinopathy, mural cells are absent from the vessel maturation process, which results in abnormal vessels growing on top of the retina, which can lead to blindness. The complex mechanisms by which mural cells regulate the activity of endothelial cells is also unclear. One way to investigate this relationship would be to develop an experimental system in which mural cells and endothelial cells are separated, yet new blood vessels still develop. As this development usually happens in the early embryo, it has been a difficult experimental system to manipulate. In the December 2 issue of the Journal of Clinical Investigation, Akiyoshi Uemura and colleagues from Kyoto University, Japan, describe such a system in the retinal vasculature of a newborn mouse - an environment in which this vessel development occurs after birth.

The authors demonstrated that when they blocked the PDGF-b receptor, mural cell recruitment to the developing retinal vessels did not occur and the newly formed vessels were leaky and poorly organized. The authors then describe the partial restoration of large vessel structure, in the absence of mural cells, following the addition of angiopoietin-1 modified from its native form (Ang1*). This indicates that Ang1 is a critical regulator of the postnatal development of blood vessels in the mouse retina.

In her accompanying commentary, Patricia D'Amore from the Schepens Eye Research Institute and Harvard Medical School notes that "as the authors themselves point out, the rescue affected by the addition of Ang1* of the pericyte-free retinal vasculature was incomplete, indicating involvement of other mural-cell derived molecules in the fine-tuning of vascular networks. Thus, the association of the pericyte with the vessel accomplishes more than local Ang1 delivery".

A more clear understanding of the role of pericytes in the maintenance of normal vessel stability will be important for anti-angiogenic therapies aimed at vessel regression, such a diabetic retinopathy.
-end-
CONTACT:
Akiyoshi Uemura
Departments of Molecular Genetics, and Ophthalmology and Visual Sciences
Kyoto University
53 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507
JAPAN
Phone: 81-75-751-4162
Fax: 81-75-751-4169
E-mail: auemura@kuhp.kyoto-u.ac.jp
View this article at http://www.jci.org/cgi/content/full/110/11/1619CONTACT:
Patricia A. D'Amore
Schepens Eye Institute
Harvard Medical School
20 Staniford Street
Boston, MA 02114
USA
Phone: 617-912-2559
Fax: 617-912-0128
E-mail: pdamore@vision.eri.harvard.edu


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