The purpose of this amended RO1 proposal is to re-establish funding for the research supported by our recently completed 2-year exploratory research grant (R21 AG19365) that was responsive to PA-00-056 """"""""Skeletal Muscle Perfusion, Aging, and Cardiovascular Disease"""""""". Our R21 award work demonstrated that: 1) basal whole-leg blood flow (LBF) and vascular conductance (LVC) are 25-30% lower in men and women 65 years of age compared with young adult controls; and 2) the decreases in LBF and LVC are associated with increased tonic sympathetic nervous system (SNS) alpha-adrenergic vasoconstriction and reduced nitric oxide (NO) vasodilatory tone. Among postmenopausal women, however, those taking hormone replacement therapy (HRT) had greater LBF and LVC than their estrogen deficient peers. The primary working hypothesis of the present proposal is that HRT (transdermal estradiol) and/or a selective estrogen receptor modulator (SERM; raloxifene) will increase LBF in healthy previously estrogen deficient postmenopausal women by increasing LVC, with or without increasing systemic BF (cardiac output). Secondary hypotheses are: 1) the increases in LVC with HRT and SERM administration will be associated with an increased local vasodilatory state (increased NO bioavailability/reduced oxidative stress; decreased endothelin-1 lET-1] concentrations), and either unchanged or reduced SNS activity; and 2) the increases in LBF and LVC in response to HRT and a SERM will be greatest in women homozygous for the C allele of the estrogen receptor (ER)-a gene IVSI 401 polymorphism and least in women who are homozygous for the T allele. LBF, arterial blood pressure, LVC, cardiac output, muscle sympathetic nerve activity, plasma catecholamine concentrations, leg peak reactive hyperemia and VC, measures of local vasodilatory/vasoconstrictor influences (including flow-mediated dilation and vascular oxidative stress), and ER-alpha gene IVS1401 polymorphisms will be determined in healthy postmenopausal females before and during 2, 6, and 12 weeks of either HRT, SERM administration, or placebo control (randomized, double blind). Insight into the molecular mechanisms involved will be provided by a novel translational research approach in which eNOS, ET-1, and other protein expressions of interest will be determined from vascular endothelial cell """"""""biopsies"""""""". All experimental protocols will be conducted in the UC-Boulder General Clinical Research Center. The results should provide new insight into the effects of HRT and a SERM for augmenting LBF and LVC in estrogen deficient postmenopausal women and the underlying physiological mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG022241-04
Application #
7224851
Study Section
Special Emphasis Panel (ZRG1-OBM-2 (04))
Program Officer
Badinelli, Joanna
Project Start
2004-04-15
Project End
2010-12-31
Budget Start
2007-05-01
Budget End
2010-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$353,197
Indirect Cost
Name
University of Colorado at Boulder
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
007431505
City
Boulder
State
CO
Country
United States
Zip Code
80309
Moreau, Kerrie L; Ozemek, Cemal (2017) Vascular Adaptations to Habitual Exercise in Older Adults: Time for the Sex Talk. Exerc Sport Sci Rev 45:116-123
Seals, Douglas R (2014) Edward F. Adolph Distinguished Lecture: The remarkable anti-aging effects of aerobic exercise on systemic arteries. J Appl Physiol (1985) 117:425-39
Walker, Ashley E; Kaplon, Rachelle E; Pierce, Gary L et al. (2014) Prevention of age-related endothelial dysfunction by habitual aerobic exercise in healthy humans: possible role of nuclear factor ?B. Clin Sci (Lond) 127:645-54
Santos-Parker, Jessica R; LaRocca, Thomas J; Seals, Douglas R (2014) Aerobic exercise and other healthy lifestyle factors that influence vascular aging. Adv Physiol Educ 38:296-307
Moreau, Kerrie L; Stauffer, Brian L; Kohrt, Wendy M et al. (2013) Essential role of estrogen for improvements in vascular endothelial function with endurance exercise in postmenopausal women. J Clin Endocrinol Metab 98:4507-15
Walker, Ashley E; Kaplon, Rachelle E; Lucking, Sara Marian S et al. (2012) Fenofibrate improves vascular endothelial function by reducing oxidative stress while increasing endothelial nitric oxide synthase in healthy normolipidemic older adults. Hypertension 60:1517-23
Gavin, Kathleen M; Jankowski, Catherine; Kohrt, Wendy M et al. (2012) Hysterectomy is associated with large artery stiffening in estrogen-deficient postmenopausal women. Menopause 19:1000-7
Jablonski, Kristen L; Chonchol, Michel; Pierce, Gary L et al. (2011) 25-Hydroxyvitamin D deficiency is associated with inflammation-linked vascular endothelial dysfunction in middle-aged and older adults. Hypertension 57:63-9
Seals, Douglas R; Jablonski, Kristen L; Donato, Anthony J (2011) Aging and vascular endothelial function in humans. Clin Sci (Lond) 120:357-75
Walker, Ashley E; Seibert, Sara Marian; Donato, Anthony J et al. (2010) Vascular endothelial function is related to white blood cell count and myeloperoxidase among healthy middle-aged and older adults. Hypertension 55:363-9

Showing the most recent 10 out of 35 publications