Estrogen protects the cardiovascular system from injury by complex mechanisms that have both short- and long-term components. Longer- term estrogen actions occurs following hours of estrogen exposure and is mediated by estrogen receptors acting in the nucleus as transcription factors for growth-related genes. The rapid effects of estrogen, by contrast, occurs in a seconds-to-minutes time frame and do not require gene transcription. Project 5 of the SCOR application addresses the molecular mechanisms underlying one of the most important of these rapid effects-vasodilation. The signaling pathways underlying this non- genomic action of estrogen are incompletely understood but new data support they involve the action of nitric oxide synthase in vascular cells, elevation of nitric oxide, stimulation of vascular smooth muscle cell soluble guanylyl cyclase, and substrate phosphorylation by cGMP- dependent protein kinase (PKG). Although the key substrate(s) for PKG is unknown, new data support one likely possibility is the smooth muscle large conductance Ca2+-activated K+ (BKCa) channel. Blockade of BKCa channels in vascular rings significantly reduces estrogen-induced vasodilation, demonstrating the central role that BKCa channels in vascular rings significantly reduces estrogen-induced vasodilation, demonstrating the central role that BKCa channels play in the acute physiological response to estrogen. Experiments in Aim 1 will use BKCa channels in vascular rings significantly reduces estrogen-induced vasodilation, demonstrating the central role that BKCa channels play in the acute physiological response to estrogen. Experiments in Aim 1 will use BKCa channel activity recorded from single smooth muscle cells dissociated from mouse aorta as an assay for characterizing upstream elements in the estrogen signaling pathway that targets BKCa channels. Experiments will assess the relative contributions of endothelial and smooth muscle cells, the types of estrogen receptor involved, and the requirement for nitric oxide synthase activation. Experiments in Aim 2 will focus on the molecular mechanism by which BKCa channel activity is regulated by estrogen. We will identify the molecular variants of BKCa channel activity is regulated by estrogen. We will identify the molecular variants. variants of BKCa channels that are expressed in smooth muscles cells from mouse aorta and study the recombinant channels expressed heterologously in order to test the hypothesis that estrogen brings about BKCa channel activation through a direct PKG-dependent phosphorylation of the channel protein. Such information is essential to further understand the protective effects of estrogen on vascular tissue and may form the basis for development of new therapies for cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL063494-03
Application #
6570518
Study Section
Special Emphasis Panel (ZHL1)
Project Start
2002-02-01
Project End
2003-01-31
Budget Start
2002-02-01
Budget End
2003-01-31
Support Year
3
Fiscal Year
2002
Total Cost
$243,390
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Shearman, Amanda M; Cooper, Jackie A; Kotwinski, Paul J et al. (2006) Estrogen receptor alpha gene variation is associated with risk of myocardial infarction in more than seven thousand men from five cohorts. Circ Res 98:590-2
Demissie, Serkalem; Cupples, L Adrienne; Shearman, Amanda M et al. (2006) Estrogen receptor-alpha variants are associated with lipoprotein size distribution and particle levels in women: the Framingham Heart Study. Atherosclerosis 185:210-8
Yang, Qiong; Lai, Chao-Qiang; Parnell, Laurence et al. (2005) Genome-wide linkage analyses and candidate gene fine mapping for HDL3 cholesterol: the Framingham Study. J Lipid Res 46:1416-25
Peter, Inga; Shearman, Amanda M; Zucker, Deborah R et al. (2005) Variation in estrogen-related genes and cross-sectional and longitudinal blood pressure in the Framingham Heart Study. J Hypertens 23:2193-200
Shearman, Amanda M; Demissie, Serkalem; Cupples, L Adrienne et al. (2005) Tobacco smoking, estrogen receptor alpha gene variation and small low density lipoprotein level. Hum Mol Genet 14:2405-13
Peter, Inga; Shearman, Amanda M; Vasan, Ramachandran S et al. (2005) Association of estrogen receptor beta gene polymorphisms with left ventricular mass and wall thickness in women. Am J Hypertens 18:1388-95
Jaffe, Iris Z; Mendelsohn, Michael E (2005) Angiotensin II and aldosterone regulate gene transcription via functional mineralocortocoid receptors in human coronary artery smooth muscle cells. Circ Res 96:643-50
Mendelsohn, Michael E; Karas, Richard H (2005) Molecular and cellular basis of cardiovascular gender differences. Science 308:1583-7
Georgescu, Serban P; Li, Joyce H; Lu, Qing et al. (2005) Modulator recognition factor 1, an AT-rich interaction domain family member, is a novel corepressor for estrogen receptor alpha. Mol Endocrinol 19:2491-501
Shearman, Amanda M; Cooper, Jackie A; Kotwinski, Paul J et al. (2005) Estrogen receptor alpha gene variation and the risk of stroke. Stroke 36:2281-2

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