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Regulation and actions of insulin-like growth factor binding proteins in vascular smooth muscle cells
Linköping University, Department of Biomedicine and Surgery, Cell biology. Linköping University, The Institute of Technology.
1999 (English)Licentiate thesis, comprehensive summary (Other academic)
Abstract [en]

Insulin-like growth factor-I (IGF-I) has multiple actions on vascular smooth muscle cell (VSMCs) function. In the circulation and in extracellular fluids, IGF-I is complexed to high affinity IGF-binding proteins (IGFBPs), which modulate IGF-I bioactivity. The present study focused on expression and regulation of IGFBPs in VSMCs. and how they modulate IGF-1 effects in these cells.

Rar VSMCs expressed mRNAs for IGFBP-2, -4 and -6, while human VSMCs expressed mRNAs for IGFBP-2, -3, -4, -5 and -6 as determined by solution hybridization. IGF-1 (10-8 M) increased and angiotensin TI (AII, 10-6 M) decreased IGFBP-2 and IGFBP-4 mRNA in rat VSMCs. Furthermore, AII and All and 1GF-I in combination increased IGF-I receptor mRNA and All decreased IGF-1 mRNA. We detected endogenous 1GFBP-2 and IGFBP-4 by Western immuno blot in concentrated conditioned medium of rat VSMCs. IGF-I did not affect steadystate levels of IGFBP-2 and -4, but increased the amount of fragments of these IGFBPs. Exogenously added IGFBP-2 and -4 were minimally degraded in serum free conditioned medium for up to 72h in the presence of VSMCs, but immunoreactive bands of the intact IGFBPs disappeared in the presence of IGF-I. We detected IGFBP-2, -4, -5 and -6 in concentrated conditioned medium of human VSMCs.

IGFBP-1 and IGFBP-4 inhibited 1GF-1 (1 nM) induced DNA synthesis in rat VSMCs with IC50 values of 1.6 and 6.2 nM respectively, and they also inhibited IGF-I induced protein synthesis. IGFBP-2, if preincubated with IGF-I, also acted inhibitory on IGF-I action. IGFBP-1, -3 and- 4 (1.4-2.0 nM) inhibited IGF-I (I nM) induced DNA synthesis in human VSMCs, while IGFBP-2, -5 and -6 had no effects in these concentrations.

IGF-I and AII had additive effects on DNA- and protein synthesis in rat VSMCs and these effects occurred at doses, at which the peptides added alone initiated DNA synthesis. Losartan blocked the synergistic effects and IGFBP-1, which inhibited IGF-I action, was not able to inhibit the action of AII.

In conclusion, rat and human VSMCs express IGFBP-2, -4 and -6, but not IGFBP-1. The results on IGFBP-3 and IGFBP-5 are inconsistent. IGFBP-1, -3 and -4 act at physiological concentrations inhibitory on IGF-I stimulated effects. IGFBP-2 and IGFBP-4 are metabolized by proteases from rat and human VSMCs and the degradation of these IGFBPs is enhanced by IGF-I. There is an interaction of AII and the IGF-system in VSMCs and IGF-I and All have additive effects on DNA- and protein synthesis in these cells.

Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 1999. , 53 + papers p.
Linköping Studies in Health Sciences. Thesis, ISSN 1100-6013 ; 40
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-25729Local ID: 10107ISBN: 91-7219-327-1OAI: diva2:246277
1999-01-29, Administrationsbyggnadens aula, Universitetssjukhuset, Linköping, 09:00 (Swedish)

Papers included in theses from 1999 and older are not registered.

Available from: 2009-10-08 Created: 2009-10-08 Last updated: 2013-12-19

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