Abstract

Interactions of vascular endothelium and insulin-like growth factors (IGFs) are complex and poorly understood. In vivo, the vascular endothelium is involved in transport of IGFs from the bloodstream to tissue. In vitro, endothelial cells have IGF receptors, respond metabolically to IGF, and synthesize several specific IGF binding proteins (IGFBPs). Endothelial cell (EC)-derived IGFBP-4 is a potent inhibitor of collagen and proteoglycan synthesis; when perfused through isolated hearts, IGFBP-4 has unique subendothelial localization in connective tissue elements. The applicant proposes to: 1) identify more completely EC IGFBPs; 2) for EC EGFBP-4, determine mechanisms of inhibitory actions, tissue distribution, and effect of diabetes; 3) determine effect of glycosylation on IGFBP-3 and -4 functional properties; 4) determine regulation of EC IGFBPs in vitro; 5) develop a perfused organ preparation that will allow analysis of effects of specific IGFBPs on IGF bioactivity; and 6) determine effect of diabetes on production of EC IGFBPs and transcapillary permeability to IGF and IGF-IGFBP complexes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK025421-18A1
Application #
2391320
Study Section
Endocrinology Study Section (END)
Program Officer
Linder, Barbara
Project Start
1979-04-01
Project End
2001-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
18
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242

  Publications

Dake, Brian L; Boes, Mary; Bach, Leon A et al. (2004) Effect of an insulin-like growth factor binding protein fusion protein on thymidine incorporation in neuroblastoma and rhabdomyosarcoma cell lines. Endocrinology 145:3369-74
Boes, Mary; Dake, Brian L; Booth, Barbara A et al. (2003) IGF-I and IGFBP-3 transport in the rat heart. Am J Physiol Endocrinol Metab 284:E237-9
Booth, B A; Boes, M; Dake, B L et al. (2002) IGFBP-3 binding to endothelial cells inhibits plasmin and thrombin proteolysis. Am J Physiol Endocrinol Metab 282:E52-8
Boes, M; Dake, B L; Booth, B A et al. (2002) Structure-function relationships of insulin-like growth factor binding protein 6 (IGFBP-6) and its chimeras. Growth Horm IGF Res 12:91-8
Knudtson, K L; Boes, M; Sandra, A et al. (2001) Distribution of chimeric IGF binding protein (IGFBP)-3 and IGFBP-4 in the rat heart: importance of C-terminal basic region. Endocrinology 142:3749-55
Oltman, C L; Kane, N L; Gutterman, D D et al. (2000) Mechanism of coronary vasodilation to insulin and insulin-like growth factor I is dependent on vessel size. Am J Physiol Endocrinol Metab 279:E176-81
Booth, B A; Boes, M; Dake, B L et al. (2000) Effect of IGFBP-derived peptides on incorporation of(35)SO(4)into proteoglycans. Growth Horm IGF Res 10:224-9
Boes, M; Dake, B L; Booth, B A et al. (1999) Connective tissue growth factor (IGFBP-rP2) expression and regulation in cultured bovine endothelial cells. Endocrinology 140:1575-80
Booth, B A; Boes, M; Dake, B L et al. (1999) Isolation and characterization of plasmin-generated bioactive fragments of IGFBP-3. Am J Physiol 276:E450-4
Sandra, A; Boes, M; Dake, B L et al. (1998) Infused IGF-I/IGFBP-3 complex causes glomerular localization of IGF-I in the rat kidney. Am J Physiol 275:E32-7

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