Summary of Research Project Results under JSPS FY2003
"Research for the Future Program"

1.Research Institution Kyoto University
2.Research Area Life Sciences
3.Research Field Angiogenesis and Vascular Development Control
4.Term of Project FY 1999 - FY 2003
5.Project Number 99L01302
6.Title of Project Control of Tissue Vascularity and its Molecular Mechanism

7.Project Leader
Name Institution,Department Title of Position
Yuji ,Hiraki Kyoto University, Institute for Frontier Medical Sciences Professor

8.Core Members

Names Institution,Department Title of Position
Mikio,Furuse Kyoto University, Graduate School of Medicine Associate Professor

9.Summary of Research Results

In tissues of mesenchymal origin, the vasculature is usually well developed. However, there are certain hypovascular tissues that exhibit powerful anti-angiogenic resistance, implying the presence of tissue-type specific inhibitors of angiogenesis. Hyaline cartilage has been well known to be an example of such anti-angiogenic tissues. We previously identified chondromodulin-I (ChM-I) as a novel cartilage-specific angiogenesis inhibitor of angiogenesis in fetal mammalian cartilage. ChM-I is specifically expressed in the avascular regions of the growth-plate and cartilaginous bone rudiments in embryos. As a main subject of this project, we succeeded in the production of bioactive recombinant human ChM-I (rhChM-I), with which we established the anti-tumor activity of ChM-I in vivo and the anti-rheumatoid activity as well. We also found that ChM-I was a bone remodeling factor, as suggested by the analysis mice lacking the gene of ChM-I. We then extended our analysis on the control of tissue vascularity in light of "anti-angiogenic barrier defined by expression of ChM-I," which led us to find a novel type II transmembrane protein, tenomodulin (TeM), having a domain homologous to ChM-I at its C-terminus. TeM was expressed in other hypovascular structures within mesenchyme, such as the epimysium, tendon and ligaments. The other subject of this project was the investigation on the barrier function of tight junctions formed between vascular endothelial cells. For this purpose, we generated mice lacking the gene of claudin-5, a major adhesion molecule of tight junctions in brain endothelial cells. In the brain of claudin-5-deficient mice, the blood-brain barrier (BBB) against small molecules (<1000 D) was impaired although the development and morphology of blood vessels were not affected. This finding not only provided a new insight into the basic molecular physiology of the BBB, but also opened a way to deliver potential drugs across the BBB into the central nervous system.

10.Key Words
(1)Angiogenesis Inhibitor  (2)Chondromodulin-I  (3)Tenomodulin 
(4)Bone Remodeling Factor  (5)Tumor Angiogenesis  (6)Rheumatoid Arthritis 
(7)Tight Junction  (8)Claudin  (9)Vascular Permeability