The regulation of human vascular smooth muscle extracellular matrix protein production by alpha- and beta-adrenoceptor stimulation.
OBJECTIVE
The sympathetic nervous system (SNS) is commonly activated in hypertension; however, the role of SNS activation in the pathogenesis of cardiovascular structural changes remains poorly defined. In particular, the effect of adrenergic stimulation on extracellular matrix (ECM) protein production by human cardiovascular cells is unknown. The present study thus investigated the direct effect of adrenergic stimulation on ECM protein production by cultured human vascular smooth muscle (VSM) cells.


RESULTS
Exposing human VSM cells to norepinephrine increased collagen protein production by 42%, P < 0.01, when compared to control (unstimulated) cells. This effect was mediated by the alpha1-adrenoceptor, since it was inhibited by the selective alpha1-adrenoceptor antagonist; prazosin (2 micromol/l) and reproduced by the selective alpha1-adrenoceptor agonist; phenylephrine (10 micromol/l). In contrast, beta-adrenoceptor stimulation - isoprenaline (1 micromol/l) or norepinephrine (10 micromol/l) + prazosin (2 micromol/l) - inhibited collagen production by 12%, P < 0.01. This inhibitory effect was mediated via the beta1-adrenoceptor, since it was blocked by atenolol (beta1-adrenoceptor antagonist) but not butoxamine (beta2-adrenoceptor antagonist). Fibronectin, another ECM protein, was similarly regulated by alpha- and beta-adrenoceptor stimulation. Transforming growth factor beta1 (TGFbeta1) mRNA expression by human VSM cells was also significantly influenced by adrenergic stimulation, being increased by phenylephrine (alpha-agonist) and inhibited by isoprenaline (beta-agonist).


CONCLUSIONS
These results uniquely demonstrate the capacity for adrenergic stimulation to directly modulate TGFbeta1 expression and ECM protein synthesis by the human cardiovascular system.
O'Callaghan
Christopher J
CJ
Department of Clinical Pharmacology, Austin and Repatriation Medical Centre, Heidelberg, Australia.
Williams
Bryan
B
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis* / Q000187:drug effects*; D005353:Fibronectins / Q000096:biosynthesis / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000098:blood supply* / Q000166:cytology / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D012333:RNA, Messenger / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000187:drug effects; D053773:Transforming Growth Factor beta1
D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D012333:RNA, Messenger; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D010656:Phenylephrine; D011433:Propranolol; D007545:Isoproterenol; D009638:Norepinephrine; D011224:Prazosin