The relationship of cyclic AMP levels and collagen synthesis in vascular smooth muscle cells following estrogen or beta adrenergic treatment

Date of Completion

January 2003


Health Sciences, Pharmacology




The use of estrogens in postmenopausal women has recently become extremely controversial. Estrogen replacement therapy has been used for many years to slow the progression of atherosclerosis. Recent clinical studies have shown that menopausal women on Hormone Replacement Therapy (HRT) have higher incidences of myocardial infarctions (MI) and strokes than their counterparts without the therapy. Other studies have demonstrated that disrupting the structural integrity of advanced atherosclerotic lesions by decreasing its collagen content could result in lesion rupture, which may culminate in clot formation on the ruptured lesion. Within lesions, vascular smooth muscle cells (VSMCs) actively synthesize collagen and other types of extracellular matrix proteins during atherogenesis. Estrogen, through activation of the second messenger cAMP, can attenuate collagen synthesis in VSMCs and promote reduction of collagen content within lesions. ^ Incubation of Rp-cAMPs, a PKA inhibitor, blocked estrogen's ability to inhibit collagen synthesis in VSMCs, suggesting that estrogen induced cAMP activates the cAMP-PKA pathway in VSMCs. Co-incubation of VSMCs with estrogen and phophodiesterase (PDE) inhibitors cilostamide or Ro-20-1724 had an additive effect on CAMP levels and inhibition of collagen synthesis. Co-incubation of VSMCs with estrogen and forskolin, an adenylyl cyclase stimulator, also had an additive effect on cAMP levels and attenuation of collagen synthesis. Co-incubation of VSMCs with estrogen and a beta-adrenergic agonist, isoproterenol or terbutaline had an additive effect on cell cAMP levels but no additive effect on inhibition of collagen synthesis. VSMCs which were treated with terbutaline had a significantly higher amount of their CAMP located extracellularly compared to estrogen treated cells. The different distribution patterns of cAMP seen in terbutaline and estrogen treated cells may explain why beta agonists did not attenuate collagen synthesis in VSMCs. These results of our studies clearly demonstrate that not all agents which elevate cAMP inhibit collagen synthesis in VSMCs. Our data also suggests that the combination of those agents which have an additive effect with estrogen could have negative effect on the stability of existing atherosclerotic lesions by inhibiting collagen synthesis. ^