Glucocorticoid inhibition of vascular smooth muscle cell proliferation: influence of homologous extracellular matrix and serum mitogens.

Abstract

We examined the influence of glucocorticoid hormones on the proliferation of cultured adult bovine aortic smooth muscle cells (BASM) using both primary mass cultures and a cloned strain . Cloned BASM cells maintained on plastic culture dishes were inhibited by -40% by dexamethasone treatment but showed no inhibition when grown on homologous extracellular matrix (ECM) coated dishes. Dexamethasone inhibited growth of primary cultures by 73% on plastic and by 45% on ECM . The inhibitory effect was specific for the glucocorticoids, dexamethasone, corticosterone, and cortisol and was not observed with progesterone, aldosterone, estradiol or 17-a OH progesterone .In cloned cells, the abolition of glucocorticoid inhibition by ECM was independent of seeding density and serum concentration . The inhibition on plastic was dependent on serum concentrations >1% and resulted in both a slow rate of proliferation and a lower saturation density . A specific subset of peptides detected on two-dimensional gels was induced by glucocorticoids under growth inhibitory conditions but was not induced when the cells were grown on ECM .Primary cultures grown on ECM and exposed to Dulbecco's modified Eagle's Medium (DME) containing high density lipoprotein and transferrin grew at 40% of the rate observed for cultures exposed to DME with 10% serum . Both conditions showed growth inhibition of 70% in the presence of dexamethasone . The addition of epidermal and platelet-derived growth factors in DME containing high density lipoprotein and transferrin to cells grown on ECM resulted in growth rates comparable to that observed with cultures exposed to 10% serum and were inhibited 45% by dexamethasone . These results suggest that glucocorticoids inhibit smooth muscle proliferation by decreasing the sensitivity of the cells to mitogenic stimulation by high density lipoprotein when the cells are maintained on a homologous substrate .

Identification of a Novel Dexamethasone-Sensitive RNA-Destabilizing Region on Rat Monocyte Chemoattractant Protein 1 mRNA

“…In SMC culture, Dex has been shown to inhibit cell cycle progression, mitogen-induced proliferation, protein synthesis, and PDGF A-chain expression (31,39,41,50). Although the predominant concentration used for most studies has been 100 nM, maximum effects have been seen with as little as 10 nM (31).…”

“…In SMC culture, Dex has been shown to inhibit cell cycle progression, mitogen-induced proliferation, protein synthesis, and PDGF A-chain expression (31,39,41,50). Although the predominant concentration used for most studies has been 100 nM, maximum effects have been seen with as little as 10 nM (31). Inhibition of SMC growth has most often employed a 24-h pretreatment; however, recent studies have suggested that 6 to 8 h may be necessary to effectively inhibit vascular SMC growth (50) and as little as 1 h may suffice to inhibit airway SMC proliferation (58).…”

Preventing local regeneration of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 enhances angiogenesis

“…It has also been proposed that glucocorticoid effects are mediated by inhibition of endothelial VEGF transcription and endothelial nitric oxide production (19,50). However, in keeping with a role for 11␤HSD-1, the effect of glucocorticoids may be mediated within vascular smooth muscle, where inhibition of matrix metalloproteinase production (51) may alter the efficacy of endothelium-dependent new vessel formation, and antiproliferative effects (20) may attenuate formation of vessel walls around endothelial cell buds.…”

“…Glucocorticoids have diverse effects on vascular function, altering vasoconstrictor responses (19), impairing endotheliumdependent vasodilatation (19), and inhibiting inflammation and cell proliferation (20,21). We recently reported studies of vascular function in knockout mice deficient in either 11␤HSD isozyme (22).…”

Glucocorticoids and Cardiovascular Disease

“…Similar pathological processes may also be relevant in the spontaneous formation of occlusive plaques. On the basis that glucocorticoids are antiinflammatory and have anti-proliferative (138)(139)(140) and anti-migratory (141) effects on smooth muscle cells, they have been employed to prevent restenosis (16, 142). Systemic administration was effective in many animal models (reviewed in (16)).…”