The vascular endothelium, in vivo, occupies a critical anatomic and physiologic position as the initial fixed surface with which the circulation comes in contact. Endothelial dysfunction and abnormalities of IGF physiology characterize several disease states, including both human and animal models of diabetes mellitus. The interactions of the vascular endothelium with the insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are complex and poorly understood. Of the six IGFBPs, IGFBP-3 is of particular interest, since it is present in the highest concentration in the circulation and is synthesized by endothelial cells in vitro and in vivo. Furthermore, the vascular endothelium is exposed to several physiologically important growth factors and cytokines, such as IGF, TGF-beta, TSH, FSH, TNF-alpha, PDGF, and bFGF, several of which regulate synthesis of IGFBP-3 by increasing intracellular levels of cAMP. The long-term goals of this proposal are: 1) to determine if the cAMP mediated regulation of endothelial IGFBP-3 mRNA occurs at the level of gene transcription and /or mRNA stability; 2) to define cis-acting element(s) that confer cAMP responsiveness in the IGFBP-3 gene; and 3) to identify and characterize the trans-acting factor(s) that bind to the sequence element(s). The studies will be carried out on cultured bovine endothelial cells. Currently, therapy with IGF-1 and IGF-1/IGFBP-3 complexes are being tested in a number of clinical conditions including diabetes mellitus, catabolic states, growth hormone insensitivity, and osteoporosis. It is hoped that the results of the proposed studies, by defining some of the mechanisms involved in endothelial IGFBP-3 regulation, will contribute to our understanding of how the interactions of the IGFs and the vascular endothelium impact on the pathogenesis as well as therapy of specific human diseases.
| Erondu, N E; Nwankwo, J; Zhong, Y et al. (1999) Transcriptional and posttranscriptional regulation of insulin-like growth factor binding protein-3 by cyclic adenosine 3',5'-monophosphate: messenger RNA stabilization is accompanied by decreased binding of a 42-kDa protein to a uridine-rich domain in the Mol Endocrinol 13:495-504 |
