Carl P. Weiner, M.D.
Laboratory of Hormonal Regulation of the Cardiovascular System
Our laboratory pursues two main lines of study. In the first, we study the role of sex hormones in modulating endothelial function and how endothelium and smooth muscle-derived substances alter vascular reactivity during pregnancy. Further, we are investigating the effect of chronic sex hormone replacement on vascular function and gene expression. Pregnancy causes profound changes in the cardiovascular system. Both maternal intravascular blood volume and cardiac output increase and blood flow is redistributed to organs whose functions are crucial for a successful outcome. After delivery, the cardiovascular system readapts to its prepregnancy state. The mechanisms mediating these profound cardiovascular adaptations are poorly understood but are likely mediated by hormonal modulation of gene expression during the gestational period. We are particularly interested in nitric oxide, a potent endothelium-derived vasodilator, K+ channels and G-protein coupling of receptors on the regulation of vascular smooth muscle function as well as their role in modulating specific organ function such as the uterus, placenta, brain, heart, and kidney. Our approach has been two fold: 1) measuring the functional responses of isolated blood vessels, heart and uterine strips, and 2) measuring gene expression during pregnancy and sex hormone replacement in a variety of organs. In the second main line of investigation, we seek the mechanism by which uterine quiescence is maintained during pregnancy. For both areas of study, we utilize several methodologies such as enzymatic assays, reverse transcriptase PCR, quantitative PCR, ribonuclease protection assay, Northern and Western blotting, and in situ hybridization. We have demonstrated that estrogen induces the transcription of eNOS and nNOS, and that it’s effect of reducing constrictor responsiveness of the coronary artery and increased expression of nitric oxide synthase mRNA of brain, uterus, heart, skeletal muscle and kidney is dose dependent. The beneficial effect on the cardiovascular system occurs at physiological levels of estrogen but is inhibited at higher doses. This has important clinical implications regarding the dose and duration of estrogen for hormone replacement therapy following the menopause period and in understanding the role of estrogen in modulating cardiovascular adaptations during pregnancy. We have demonstrated that the chorion of guinea pigs and humans produces a C-NP like substance that stimulates the production of myometrial particulate guanylate cyclase. We have further shown that the plasma of the mother and fetus contain an inhibitory factor which blocks the chorion’s effect on cGMP. The amount of the substances produced are gestationally regulated.
Recent Publications:Weiner CP, Knowles RG, Nelson SE 1994 Pregnancy increases cGMP in the myometrium independent of nitric oxide synthesis. Endocrinology 135:2473-2478.
Weiner CP, Knowles RG, Moncada S 1994 Induction of nitric oxide synthases early in pregnancy. Am J Obstet Gynecol 171:838-843.
Moro MA, Aguan K, Lizasoain I, Leza JC, Thompson L, Knowles RG, Weiner CP 1997 Modulation of constitutive nitric oxide synthase activity and expression by estradiol. Endocrinology, in press.
Thompson LP, Weiner CP 1997 Long-term estradiol replacement decreases contractility of guinea pig coronary arteries to the thromboxane mimetic U46619. Circulation 95:709-714
