Abstract
Rat aorta smooth muscle cells which express all three alpha 1-adrenoreceptors (alpha 1A, alpha 1B and alpha 1D) were used to determine the effect of stimulation of alpha 1-adrenergic receptor subtypes on cell growth. "Combined" alpha 1-adrenoreceptor subtype stimulation with norepinephrine alone caused a concentration-dependent, prazosin-sensitive increase in protein content and synthesis: 48 h of stimulation at 1 microM increased cell protein to 216 +/- 40% of time-matched controls (p = 0.008) and RNA to 140 +/- 13% (p = 0.03); protein synthesis increased to 167 +/- 13% (p < 0.01) after 24 h. Stimulation with norepinephrine plus the selective alpha 1A/alpha 1D antagonist 5-methylurapidil produced greater increases in alpha-actin mRNA (270 +/- 40% at 8 h; p = 0.007), total cell protein (220 +/- 45% at 24 h; p = 0.004), and RNA (135 +/- 8% at 24 h; p = 0.01). These effects were prevented by pretreatment with the selective alpha 1B antagonist chloroethylclonidine. Comparable results were obtained for intact aortae. Stimulation with norepinephrine plus 5-methylurapidil increased (p < 0.05) tissue protein, RNA, dry weight, and alpha-actin mRNA; and as in culture cells, combined stimulation with norepinephrine alone attenuated these responses. By comparison, adventitia (fibroblasts) was unaffected. Removal of endothelial cells had no effect. alpha 1B mRNA decreased by 42 +/- 12% (p = 0.01) in cultured cells during combined alpha 1-adrenoreceptor stimulation and by 23 +/- 8% (p = 0.03) for intact aorta. alpha 1D and beta-actin mRNA were unchanged in cultured cells, aorta media, and adventitia. These findings suggest that prolonged stimulation of chloroethylclonidine-sensitive, possibly alpha 1B-adrenoceptors induces hypertrophy of arterial smooth muscle cells and that stimulation of 5-methylurapidil-sensitive, non-alpha 1B-adrenoreceptors attenuates this growth response.
Highlights
Well as hypertrophy of the vascular wall in hypertensive animals (4 –7)
The principal findings of this study were that stimulation of aorta SMC ␣1ARs over 24 – 48 h doubled the per cell amount of RNA, protein, and sarcomeric ␣-actin mRNA, while not affecting cytoskeletal -actin mRNA or inducing cell proliferation
Vena cava SMCs did not display this ␣1-mediated “hypertrophy,” nor did they exhibit the decreased ␣1BAR mRNA that was evidenced by aorta SMCs
Summary
Well as hypertrophy of the vascular wall in hypertensive animals (4 –7). There is considerable evidence that smoking, stress, and hypertension, which are key risk factors for atherosclerosis and hypertrophic vascular disease, are associated with elevated plasma catecholamines [8, 9]. Rat aorta has been shown recently to express ␣1A (formerly denoted “␣1C”) mRNA (26 –29) Given this multiplicity of ␣1AR expression, the purpose of the present study was first to examine both in vitro and in situ, the effects of combined stimulation of the ␣1AR subtypes with NE alone on proliferation-independent growth, and expression of sarcomeric ␣-SMC-actin and cytoskeletal -actin mRNAs by arterial and venous SMCs. Second, effects of combined stimulation were compared with those during treatment with NE plus antagonists, 5-methylurapidil (5-MU, selectivity ϭ ␣1A Ͼ ␣1D Ͼ ␣1B) to favor ␣1B stimulation and after pretreatment with chloroethylclonidine (CEC, selectivity ϭ ␣1B Ͼ ␣1D Ͼ ␣1A) to select for stimulation of non-␣1BARs. The results suggest, in both cultured aorta SMCs and intact aorta media, that stimulation of CEC-sensitive ␣1ARs (possibly ␣1B) induces hypertrophy of aorta SMCs and that stimulation of 5-MU-sensitive, non␣1BARs antagonizes this response. ␣1-Adrenoreceptors and Cell Growth may participate in both normal vascular growth and remodeling and in vascular hypertrophic diseases
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