Date of Completion
Health Sciences, Pharmacology
Langer, Ronald O.
Field of Study
Doctor of Philosophy
The use of estrogens in postmenopausal women has become controversial. Estrogen replacement therapy has been used for many years to slow the progression of atherosclerosis. However, recent clinical studies have shown that menopausal women on hormone replacement therapy have higher incidences of myocardial infarctions and strokes than their counterparts without the therapy. Other studies have demonstrated that a decrease in collagen content in advanced atherosclerotic lesions may weaken the structural integrity of these lesions, resulting in rupture and clot formation. 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, may attenuate collagen synthesis in VSMCs and may promote reduction of collagen content in lesions.
Incubation with Rp-cAMPs, a PKA inhibitor, blocked estrogen's ability to
inhibit collagen synthesis in VSMCs. This suggests that estrogen, through stimulation of cAMP, may activate the cAMP-PKA pathway in VSMCs. Treatment of VSMCs with estrogen and phophodiesterase inhibitors, cilostamide or Ro-20-1724, had an additive effect on increasing cAMP levels and on inhibiting collagen synthesis. VSMCs treated with estrogen and forskolin, an adenylyl cyclase stimulator, also had an additive effect on increasing cAMP levels
and on attenuating collagen synthesis. When VSMCs were treated with both estrogen and a beta-adrenergic agonist, isoproterenol or terbutaline, there was an additive effect on cellular cAMP levels although the observed decrease in collagen synthetic rates were the same as observed in estrogen treated cells. VSMCs, which were treated with terbutaline, had a significantly higher amount of cAMP located extracellularly compared to estrogen treated cells. The different distribution patterns of cAMP observed in terbutaline and estrogen treated cells may explain why beta agonists may not attenuate collagen synthesis in VSMCs. These results clearly demonstrate that not all agents, which elevate cAMP, may inhibit collagen synthesis in VSMCs. Our data also suggest that the combination of agents, which have an additive effect with estrogen, may have a negative effect on the stability of existing atherosclerotic lesions through the inhibition of collagen synthesis.
Dimopoulos, George John, "The relationship of cyclic AMP levels and collagen synthesis in vascular smooth muscle cells following estrogen or beta-adrenergic treatment" (2003). Doctoral Dissertations. 2646.