The Principal Investigator recently discovered, purified, and cloned and sequenced a novel 18 kD mitogenic protein from bovine uterus which is closely related to, but distinct from bFGF. This growth factor, termed pleiotrophin (PTN) or heparin-binding growth factor (HBGF)-8, displays extraordinary conservation of cDNA sequence between 3 mammalian species and is widely expressed and developmentally regulated in the fetus and newborn. Following birth, the levels of this growth factor decline dramatically. cDNA cloning indicate the relationship between PTN and the MK gene, a recently described retinoic acid induced gene of unknown function identified in differentiating teratocarcinoma cells. Thus, PTN and MK are thought to be the first members of a new family of developmentally regulated cytokines active in the tissue of fetal and developing mammals. Preliminary data by the Principal Investigator demonstrate that the pure bovine PTN protein may be angiogenic since it stimulates 3H-thymidine uptake into cultures of fetal bovine heart endothelial cells. The aim of the studies described in this grant proposal is to investigate if PTN mRNA is expressed in developing vascular structures such as the heart and blood vessels of the mammalian fetus and newborn, and whether this expression is developmentally regulated. Studies will also be performed to confirm the mitogenic effects of PTN on various cell types of developing blood vessels and heart. The role of Vitamin A in blood vessel development will be studied. The Principal Investigator also aims to identify the cell surface on responsive vascular cells which mediates the angiogenic effect of PTN, and to purify this receptor. Detailed investigation of the role of PTN in development and enlargement of vascular structures will, when complete, identify important mechanisms of angiogenesis in the developing mammal and also have bearing on regional vascular malformations.