The age adjusted incidence of coronary artery disease of premenopausal women lags approximately ten years behind that of men. After menopause, the incidence rises at a rate similar to that of men. This suggests a hormone, possibly estrogen protects the coronary arteries and heart by unknown mechanisms. In preliminary study, we have shown diminished contraction to thromboxane of coronary artery rings prepared from female guinea pigs compared to males after the inhibition of guanylate cyclase. Further, equal concentrations of cGMP produce greater relaxation of thromboxane-contracted coronary arteries from females compared to males. These findings suggest a sexual dimorphism in cGMP synthesis/breakdown. Nitric oxide (NO), an autacoid with diverse roles works by activating cGMP. NO stimulates endothelial but inhibits smooth muscle cell proliferation. We have shown that estradiol increases the activity of nitric oxide synthase (NOS) through increased gene transcription. These findings suggest estrogen may provide dual protection against coronary artery disease. First, by increasing endothelium-derived NO, estrogen minimizes the response to contractile agonists released during thrombus formation. And second, by inhibiting vascular smooth muscle (VSM) cell and stimulating endothelial cell proliferation, estrogen slows the development of atherosclerosis. Thus, we hypothesize that estrogen exerts a protective effect on the coronary circulation via its augmentation of NOS and guanylate cyclase activities. The experiments proposed to test this hypothesis utilize isolated hearts, coronary arteries, and cultured cells to study the physiology, biochemistry and molecular biology of gender differences. First, we will examine the role of the NO/cGMP pathway in regulating intracellular Ca2+ and coronary artery reactivity by estrogen using both biochemical measurements of NOS and guanylate cyclase and by the application of specific inhibitors to isolated coronary artery rings. Second, we will confirm the induction of the nos-genes by estradiol and determine which nos-genes are induced using Northern/Dot blot analyses. Third, we will localize the site of nos-mRNA synthesis by in situ hybridization using guinea pig sequence specific probes developed in our laboratory. Finally, since elastin has been shown to contribute to arterial wall thickening, we will investigate the effect of estrogen on elastin gene induction as well as cell growth and proliferation of VSM. The investigation will be carried out over five years using sexually mature (intact and surgically castrated) male and female guinea pigs and will provide new evidence for the role of estrogen in modulating coronary artery reactivity via the NO/cGMP pathway.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL051735-04
Application #
2029056
Study Section
Special Emphasis Panel (ZHL1-CSR-S (S2))
Project Start
1993-12-01
Project End
1997-11-30
Budget Start
1996-09-30
Budget End
1996-11-30
Support Year
4
Fiscal Year
1996
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Carvajal, Jorge A; Thompson, Loren P; Weiner, Carl P (2003) Chorion-induced myometrial relaxation is mediated by large-conductance Ca2+-activated K+ channel opening in the guinea pig. Am J Obstet Gynecol 188:84-91
Carvajal, J A; Buhimschi, I A; Thompson, L P et al. (2001) Chorion releases a factor that inhibits oxytocin-stimulated myometrial contractility in the pregnant guinea pig. Hum Reprod 16:638-43
Carvajal, J A; Aguan, K; Thompson, L P et al. (2001) Natriuretic peptide-induced relaxation of myometrium from the pregnant guinea pig is not mediated by guanylate cyclase activation. J Pharmacol Exp Ther 297:181-8
Thompson, L P; Weiner, C P (2001) Pregnancy enhances G protein activation and nitric oxide release from uterine arteries. Am J Physiol Heart Circ Physiol 280:H2069-75
Thompson, L P; Pinkas, G; Weiner, C P (2000) Chronic 17beta-estradiol replacement increases nitric oxide-mediated vasodilation of guinea pig coronary microcirculation. Circulation 102:445-51
Tan, E; Gurjar, M V; Sharma, R V et al. (1999) Estrogen receptor-alpha gene transfer into bovine aortic endothelial cells induces eNOS gene expression and inhibits cell migration. Cardiovasc Res 43:788-97
Baylis, S A; Strijbos, P J; Sandra, A et al. (1999) Temporal expression of inducible nitric oxide synthase in mouse and human placenta. Mol Hum Reprod 5:277-86
Van den Veyver, I B; Ni, J; Bowles, N et al. (1998) Detection of intrauterine viral infection using the polymerase chain reaction. Mol Genet Metab 63:85-95
Weiner, C P (1997) Umbilical venous pressure is unaltered by severe, early-onset growth restriction. Fetal Diagn Ther 12:348-52
Yankowitz, J; Li, S; Weiner, C P (1997) Polymerase chain reaction determination of RhC, Rhc, and RhE blood types: an evaluation of accuracy and clinical utility. Am J Obstet Gynecol 176:1107-11

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