Menopause Effects on Vascular Function
| Status: | Recruiting |
|---|---|
| Conditions: | Peripheral Vascular Disease |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 10/5/2018 |
| Start Date: | July 1, 2016 |
| End Date: | June 30, 2019 |
| Contact: | Megan Wenner, PhD |
| Email: | mwenner@udel.edu |
| Phone: | 302-831-7343 |
Mechanisms of Vascular Dysfunction in Women: Role of Estradiol
The purpose of the study is to identify the independent effect of estradiol (E2) on
endothelin-1 (ET-1) mediated vasomotor function in women. The study is the first step in
recognizing the impact of ovarian hormones on the mechanisms that regulate vascular function
in women to provide a better understanding of the cardiovascular efficacy of hormone therapy.
endothelin-1 (ET-1) mediated vasomotor function in women. The study is the first step in
recognizing the impact of ovarian hormones on the mechanisms that regulate vascular function
in women to provide a better understanding of the cardiovascular efficacy of hormone therapy.
Cardiovascular disease (CVD) is the leading cause of death in women (Roger, Go, Lloyd, Adams,
Berry, Brown, et al, 2011). Functional changes in the microvasculature occur with aging and
precede atherosclerosis, contributing to CVD (Seals, Jablonski, & Donato, 2011). Furthermore,
because of the decline in ovarian hormones during menopause, age-related impairments in
endothelial function are exacerbated in postmenopausal women (PMW). However, the safety and
efficacy of currently available hormone-based therapies remains controversial (Devi,
Sugiguchi, Pederson, Abrassart Glodowski, & Nachtigall, 2013: Miller, Black, Brinton, Budoff,
Cedars, Hodis, et al, 2009). Endothelin-1 (ET-1) is a potent vasoconstrictor produced and
released by endothelial cells and implicated in the development of atherosclerosis (Best,
McKenna, Holmes, & Lerman, 1999; Donato, Gano, Eskurza, Silver, Gates, Jablonski, et al,
2009; Ihling, Szombathy, Bohrmann, Brockhaus, Schaefer, & Loeffler, 2009). ET-1 binds to two
receptor subtypes, ET-A and ET-B (Yanagisawa, Kurihara, Kimura, Tomobe, Kobayashi, Mitsui, et
al, 1988). While both receptors are located on vascular smooth muscle (VSM) and cause
vasoconstriction, ET-B receptors are also located on the endothelium and cause vasodilation
(Gomez-Sanchez, Cozza, Foecking, Chiou, & Ferris, 1990; Haynes, 1995; Ishikawa, Ihara,
Noguchi, Mase, Mino Saeki, et al, 1994). In women, ET-1 preferentially binds to ET-B
receptors compared to ET-A receptors, supporting findings of sex differences in ET-1 receptor
responses and suggesting ET-B receptors are under hormonal control (Ergul, Shoemaker, Puett,
& Tackett, 1998; Kellogg, Liu, & Pergola, 2001; Stauffer, Westby, Greiner, Van Guilder, &
Desouza, 2010). In animal models, estradiol (E2) reduces ET-1 mediated vasoconstriction and
increases ET-B receptor mRNA (Pederson, Nielsen, Mortensen, Nilas, & Ottesen, 2008). Thus,
low levels of E2 in PMW may contribute to impaired vascular function through an ET-B receptor
mechanism. However, the interaction between E2 and ET-1 receptor responses on regulating
vascular function in women is currently unknown.
The long-term goal of the laboratory is to understand the impact of ovarian hormones on the
mechanisms that regulate vascular function in women to provide a better understanding of the
cardiovascular efficacy of hormone therapy. The study is the first step in reaching our goal;
the objective of the study is to identify the independent effect of E2 on ET-1 mediated
vasomotor function in women. The investigators will measure blood flow responses to local
heating in the cutaneous circulation during perfusion of ET-1 receptor antagonists via
microdialysis, coupled with measures of intracellular protein and receptor expression on
endothelial cells and skin punch biopsies (to assess VSM cells) collected from young and PMW
while controlling ovarian hormone exposure. Young women will be tested after suppressing
ovarian production of E2 and progesterone with a gonadotropin-releasing hormone antagonist
(GnRHant), and again after E2 administration; PMW, who are not using hormone therapy, will be
tested before and after E2 admin. The central hypothesis is that declines in E2 impair
microvascular vasodilatory function due to cellular changes in ET-B receptor expression on
endothelial and VSM cells, and that E2 administration reverses these responses.
Berry, Brown, et al, 2011). Functional changes in the microvasculature occur with aging and
precede atherosclerosis, contributing to CVD (Seals, Jablonski, & Donato, 2011). Furthermore,
because of the decline in ovarian hormones during menopause, age-related impairments in
endothelial function are exacerbated in postmenopausal women (PMW). However, the safety and
efficacy of currently available hormone-based therapies remains controversial (Devi,
Sugiguchi, Pederson, Abrassart Glodowski, & Nachtigall, 2013: Miller, Black, Brinton, Budoff,
Cedars, Hodis, et al, 2009). Endothelin-1 (ET-1) is a potent vasoconstrictor produced and
released by endothelial cells and implicated in the development of atherosclerosis (Best,
McKenna, Holmes, & Lerman, 1999; Donato, Gano, Eskurza, Silver, Gates, Jablonski, et al,
2009; Ihling, Szombathy, Bohrmann, Brockhaus, Schaefer, & Loeffler, 2009). ET-1 binds to two
receptor subtypes, ET-A and ET-B (Yanagisawa, Kurihara, Kimura, Tomobe, Kobayashi, Mitsui, et
al, 1988). While both receptors are located on vascular smooth muscle (VSM) and cause
vasoconstriction, ET-B receptors are also located on the endothelium and cause vasodilation
(Gomez-Sanchez, Cozza, Foecking, Chiou, & Ferris, 1990; Haynes, 1995; Ishikawa, Ihara,
Noguchi, Mase, Mino Saeki, et al, 1994). In women, ET-1 preferentially binds to ET-B
receptors compared to ET-A receptors, supporting findings of sex differences in ET-1 receptor
responses and suggesting ET-B receptors are under hormonal control (Ergul, Shoemaker, Puett,
& Tackett, 1998; Kellogg, Liu, & Pergola, 2001; Stauffer, Westby, Greiner, Van Guilder, &
Desouza, 2010). In animal models, estradiol (E2) reduces ET-1 mediated vasoconstriction and
increases ET-B receptor mRNA (Pederson, Nielsen, Mortensen, Nilas, & Ottesen, 2008). Thus,
low levels of E2 in PMW may contribute to impaired vascular function through an ET-B receptor
mechanism. However, the interaction between E2 and ET-1 receptor responses on regulating
vascular function in women is currently unknown.
The long-term goal of the laboratory is to understand the impact of ovarian hormones on the
mechanisms that regulate vascular function in women to provide a better understanding of the
cardiovascular efficacy of hormone therapy. The study is the first step in reaching our goal;
the objective of the study is to identify the independent effect of E2 on ET-1 mediated
vasomotor function in women. The investigators will measure blood flow responses to local
heating in the cutaneous circulation during perfusion of ET-1 receptor antagonists via
microdialysis, coupled with measures of intracellular protein and receptor expression on
endothelial cells and skin punch biopsies (to assess VSM cells) collected from young and PMW
while controlling ovarian hormone exposure. Young women will be tested after suppressing
ovarian production of E2 and progesterone with a gonadotropin-releasing hormone antagonist
(GnRHant), and again after E2 administration; PMW, who are not using hormone therapy, will be
tested before and after E2 admin. The central hypothesis is that declines in E2 impair
microvascular vasodilatory function due to cellular changes in ET-B receptor expression on
endothelial and VSM cells, and that E2 administration reverses these responses.
Inclusion Criteria:
- Young women between 18-35 years of age with regular menstrual cycles
- Postmenopausal women between 50-65 years of age and no more than 10 years past
menopause
- Non-smoking
- BMI < 30 kg/m2
- Free from known disease (heart disease, cancer, diabetes)
Exclusion Criteria:
- Current use of hormone therapy or within the past year
- Women using Depo-provera or an intra-uterine device (IUD)
- Pregnant, are planning on becoming pregnant, or are breast- feeding.
- History of stable or unstable angina
- Diabetes
- Neurological disease
- Lung disease
- Kidney or liver disease
- Cancer
- Hysterectomy
- Peripheral vascular disease
- History of blood clots
- Heart disease
- Fibroids
- High blood pressure
- Stroke
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