Cell-extracellular matrix (ECM) interactions are important in proliferative and morphogenic processes that occur in normal development as well as during wound healing. Understanding the role of specific cell-ECM interactions in the context of the vasculature is the overall goal of the research objectives in this proposal. Thrombospondin-1 (TSP1) is a trimeric, multifunctional secreted glycoprotein, involved in the regulation of a variety of physiological and pathological processes including platelet aggregation, angiogenesis, and vascular cell growth. We have recently established that low density lipoprotein receptor-related protein-1 (LRP-1) is a cell surface receptor for TSP1 and is responsible for cell-mediated endocytosis and subsequent lysosomal degradation of TSP1 in cultures vascular smooth muscle cells (SMCs) (Godyna et al., (1995) J. Cell Biol. 129:1403). The identification of LRP-1 as the endocytic receptor fro TSP1 provides an opportunity to test the biological significance of the cell-mediated catabolism of TSP1. In this application we provide preliminary evidence supporting an important role for LRP-1 in the control of TSP1 dependent regulation of SMCs and fibroblast growth. These results are consistent with our hypothesis that LRP-1 is a critical receptor in the regulation of the biological activity of TSP1 in the vasculature. The major objective of this proposal is to determine the role of TSP1 in vascular cell migration, proliferation, and apoptosis by examining the mechanism(s) and functional significance of TSP1 interaction with the cell surface; emphasizing the role of LRP-1 in regulating the turnover of TSP1.
The specific aims are: 1. To delineate the behavioral/cellular responses (e.g. mitogenesis, apoptosis, and migration) that vascular SMCs and fibroblasts exhibit following inhibition of LRP-1-mediated catabolism of TSP1. 2. To determine the mechanism(s) (e.g. activation of latent TGF-beta, direct signal transduction via cell surface receptors, and modulation of extracellular proteinase activity) that underlie the behavioral responses that cells exhibit following inhibition of LRP-1-mediated catabolism of TSP1. 3. To determine the parameters that influence LRP-1-mediated catabolism of TSP1 (e.g. growth state, cell origin, and effect of growth factors). The proposed studies will provide a better understanding of the role of TSP1 in vascular healing processes and contribute to an overall understanding of the function of the endocytic receptor, LRP-1 in regulating the biological activity of TSP1.
|Wang, Shuxia; Herndon, Mary E; Ranganathan, Sripriya et al. (2004) Internalization but not binding of thrombospondin-1 to low density lipoprotein receptor-related protein-1 requires heparan sulfate proteoglycans. J Cell Biochem 91:766-76|
|Vanguri, V K; Wang, S; Godyna, S et al. (2000) Thrombospondin-1 binds to polyhistidine with high affinity and specificity. Biochem J 347:469-73|