Wednesday, April 2, 2025
4/2/2025
Disentangling the effects of daily stress, sleep, and sex hormones on accelerated vascular aging in midlife women - PROJECT SUMMARY Cardiovascular disease (CVD) morbidity has increased by up to 30% in midlife women in the last 20 years. Increased CVD risk in midlife women is at least partially explained by declines in estradiol (E2) that occur across the menopausal transition and accelerate vascular aging. Although vascular dysfunction has been noted in early perimenopausal women, our novel preliminary data show that reductions in endothelium-dependent dilation are evident in some premenopausal midlife women, strongly suggesting that the development of endothelial dysfunction in midlife precedes the menopausal transition and thus cannot be solely explained by the loss of E2. Emerging factors that may help explain accelerated vascular aging in midlife women include greater emotional responsivity to daily stressors and greater sleep irregularity. While both common features of menopause, these dynamic constructs can vary across the menopausal transition and are independently related to disruptions in vascular homeostasis. As such, amplified emotional responsivity to daily stressors and greater sleep variability may represent novel, modifiable, biobehavioral mechanisms to help explain the inter-individual variability in the degree of vascular endothelial dysfunction in premenopausal midlife women. The objective of this proposal is to test the central hypothesis that (a) greater negative affective responsivity to daily stressors and (b) greater sleep variability will each be related to more severe declines in endothelial function in premenopausal midlife women and that these associations will be magnified during E2 suppression (simulated menopause) compared to during natural cycling. To test this, 30 pre- menopausal middle-aged women (45-55 years) will complete two ‘measurement bursts’ (randomized, crossover): one while naturally cycling and one during simulated menopause using an ovarian hormone suppression intervention [daily subcutaneous injections of a gonadotropin-releasing hormone antagonist (GnRHant; Ganirelix acetate)]. On days 1-10 of each burst, we will assess multiple dynamic aspects of daily stress processes (mobile app-based daily diary approach) and sleep health (wrist accelerometry). On days 0 and 11 (i.e., pre and post), we will use orthogonal laboratory-based techniques to examine the mechanistic regulation of microvascular endothelial function (intradermal microdialysis coupled with laser Doppler flowmetry), an approach that allows for a detailed characterization of vascular endothelial function. This multipronged, multidimensional framework will allow for a comprehensive examination of behavioral and physiological factors in the context of aging and changes in reproductive hormones to better understand subclinical CVD risk in midlife women—a priority of the Trans-NIH Strategic Plan for Women’s Health Research. The anticipated outcomes will provide proof of concept that emotional responsivity to daily stressors and sleep health are potentially potent, modifiable mechanisms contributing to inter-individual heterogeneity in vascular dysfunction in midlife women. As such, this line of inquiry is uniquely poised to inform subsequent, larger and fully powered trials to test the effects of behavioral (i.e., stress reduction, improved sleep) and/or pharmacological (i.e., hormone intervention) strategies to preserve vascular health during menopause, thereby mitigating CVD risk.
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