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Molecular and Cellular Biology, July 2003, p. 4627-4636, Vol. 23, No. 13
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.13.4627-4636.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Bone Morphogenetic Protein 4 Mediates Apoptosis of Capillary Endothelial Cells during Rat Pupillary Membrane Regression

Mari Kiyono and Masabumi Shibuya*

Department of Genetics, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

Received 2 December 2002/ Returned for modification 23 January 2003/ Accepted 27 March 2003

Programmed capillary regression is essential for development, but little is known about the mechanism behind this phenomenon. In this study, we characterized the molecular determinants of capillary regression utilizing the pupillary membrane (PM) in the newborn rat's eye. We observed in the 1-day-culture system that apoptotic endothelial cells decrease in number with the addition of a natural antagonist, Noggin, strongly suggesting the involvement of the bone morphogenetic protein (BMP) family in PM regression. In addition, the lens-conditioned medium (Lens-CM) induced apoptosis of HUVE cells and inhibited endothelial tubulogenesis, which were completely blocked by both Noggin and the BMP4-specific neutralizing antibody. Activation of BMP4 pathway in endothelial cells was confirmed by both the up-regulation of Msx genes correlated with apoptosis and the translocation of Smad1 into the nucleus. We showed a transient expression of BMP4 in Lens-CM by immunoprecipitation assay. Furthermore, the transcorneal injection of BMP4 in rats enhanced the apoptosis of PMs, while that of Noggin attenuated it. These results indicate that BMP4 pathways play pivotal roles in capillary regression in a paracrine manner between lens and PMs.

* Corresponding author. Mailing address: Department of Genetics, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan. Phone: 81-3-5449-5550. Fax: 81-3-5449-542. E-mail: shibuya{at}ims.u-tokyo.ac.jp.

Molecular and Cellular Biology, July 2003, p. 4627-4636, Vol. 23, No. 13
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.13.4627-4636.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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