Angiogenesis is a physiological process tht regulates the growth of both normal tissues and tumors. While angiogenesis is important for normal growth processes such as embryonic development and wound healing, abnormal angiogenesis is associated with proliferative diseases such as solid tumor growth and diabetic retinopathy. The goal is to understand the role of growth factors in angiogenesis. Angiogenesis is regulated in part by growth factors that stimulate the migration and proliferation of endothial cells (EC). EC growth factors have a marked affinity for heparin, a phenomenon that has greatly facilitated their purification. Heparin-Sepharose affinity chromatography was used for the first purification to homogeneity of an EC growth factor. This EC growth factor, isolated from a rat chondrosarcoma, is a cationic 18,000 molecular weight polypeptide that stimulates EC proliferation at 1 ng/m1 and induces angiogenesis in the chick chorioallantoic membrane and in the rat cornea (Shing et al, Science 223: 1296-1299, 1984). Heparin affinity chromatography has been used to purify homogeneous EC growth factor from other sources as well including hepatoma cells, cartilage and brain. Having completed angiogenic EC growth factor purification, the next phase of research will stress questions related to structure and function, immunological analysis, physiological role and mechanisms of action of EC growth factors.
The specific aims of the proposed research arre as follows: 1) to purify angiogenic EC growth factors on a large scale; 2) to analyze the structures of EC growth factors in terms of comparative amino acid sequences and multiple molecular weight forms. The sequences will be used to prepare synthetic peptides; 3) To prepare site-specific antibodies directed against synthetic peptides corresponding to EC growth factor sequences. These antibodies will be used as probes for the purposes of EC growth factor detection, quantitation and localization; 4) To test EC growth factors in vivo, especially in regards to their angiogenesis activity; 5) To investigate EC growth factor interactions with heparin-like molecules associated with EC. 6) To purify and characterize EC growth factors associated with normal embryonic development in the chick limb bud; 7) As a long range goal to study EC growth factor gene expression.
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