A. Anwar et al., Insulin-like growth factor binding protein-4 expression is decreased by angiotensin II and thrombin in rat aortic vascular smooth muscle cells, ART THROM V, 20(2), 2000, pp. 370-376
Insulin-like growth factor-I (IGF-I) is a ubiquitous peptide that regulates
cellular growth and differentiation and is involved in vascular proliferat
ive responses. The effects of IGF-I are modulated by several IGF-I binding
proteins (IGFBPs), including IGFBP-4, the main IGFBP produced by vascular s
mooth muscle cells (VSMCs). We have previously shown that angiotensin II (A
ng II)-induced and thrombin-induced mitogenesis in VSMCs is dependent on au
tocrine IGF-I. In addition, we have demonstrated that IGF-I and IGFBP-4 mRN
A levels are upregulated in the hypertensive aorta of abdominally coarcted
rats, a high-renin hypertension model. To obtain further insight into the I
GF-I system and to specifically study changes in IGFBP-4, a known inhibitor
of IGF-I action, VSMCs u ere incubated with Ang II or thrombin. Compared w
ith control, Ang II induced an 87+/-2% downregulation of IGFBP-4 mRNA level
s at 24 hours, with a 61+/-6% decrease of IGFBP-4 levels, as determined by
Western ligand blot analysis. Thrombin had the same depressor effects (87+/
-2% for the mRNA levels and 61+/-3% for the protein levels). Ang II and thr
ombin coincubation with I-125-IGFBP-4 in the conditioned media failed to re
veal any increase in fragmentation, indicating that proteolytic cleavage of
IGFBP-4 was not involved in the observed effects. Exogenous recombinant hu
man IGFBP-4 decreased thrombin-induced DNA synthesis of human aortic VSMCs
by 64%, whereas anti-IGFBP-4 antibody potentiated thrombin-induced DNA synt
hesis. These data suggest that downregulation of IGFBP-4 expression in VSMC
s may play a critical role in vascular growth response to Ang II and thromb
in in normal and diseased states, by increasing the bioavailability of IGF-
I for its cell-surface receptor.