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Department of Physiology, Midwestern University, Glendale, Arizona 85308
Vascular smooth muscle cells (VSMC) subjected to
acute or chronic stretch display enhanced growth rates in vitro and in
vivo. Clinical examples of vascular hyperplasia (e.g., systolic
hypertension and postinjury restenosis) suggest that local insulin-like
growth factor I (IGF-I) expression is enhanced. Therefore, we
investigated the role of in vitro cyclic stretch on rat VSMC IGF-I
secretion and cellular growth. In serum-free medium, cyclic stretch (1 Hz at 120% resting length for 48 h) stimulated thymidine incorporation ~40% above that seen in nonstretched cells. Graded stretch magnitude (100-125% resting length) yielded graded increases in VSMC
growth. Exogenous IGF-I increased growth of serum-starved, nonstretched VSMC in a dose-dependent manner, with maximal growth seen with 10
7 M. IGF-I secretion from
stretched cells was 20- to 30-fold greater than from those cells
cultured in a static environment. Stretch-induced increases in growth
were completely blocked on addition of anti-IGF-I and partially blocked
with platelet-derived growth factor (PDGF) antibodies and with a
tyrosine kinase inhibitor (tyrphostin-1). Finally, blockade of
stretch-activated cation channels with
GdCl3 profoundly inhibited
stretch-induced growth. We conclude that stretch increases VSMC IGF-I
secretion and that such autocrine IGF-I is required for stretch-induced
growth. PDGF and stretch-sensitive cation channels are likely
additional components of a complex pathway that regulates
stretch-induced VSMC seen in systolic hypertension and postinjury restenosis.
insulin-like growth factor I; restenosis; platelet-derived growth factor; tyrosine kinase
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