Impaired vascular function in postmenopausal women with a history of a hypertensive disorder of pregnancy: potential role of the circulating milieu-evoked mitochondrial oxidative stress

Background: Cardiovascular disease (CVD) remains the leading cause of death in postmenopausal women (PMW). A history of a hypertensive disorder of pregnancy (hxHDP) increases CVD risk, and this elevation in risk persists into the postmenopausal period. Carotid intima-media thickness (IMT), a subclinical marker of atherosclerosis, is an independent predictor of CVD in PMW. However, whether carotid IMT is greater in PMW with a hxHDP compared with PMW with a history of normotensive pregnancies (hxNP) is not clear. Vascular endothelial function is lower after menopause and is a key antecedent to atherosclerotic CVD in PMW. Excess mitochondrial reactive oxygen species (mitoROS)-related oxidative stress induced by the circulating milieu is a mechanism of endothelial dysfunction after menopause. However, it is unknown whether PMW with a hxHDP exhibit impaired endothelial function compared with PMW with a hxNP and whether circulating milieu-induced endothelial mitochondrial oxidative stress may play a role. Hypotheses: We tested the hypothesis that, compared with PMW with a hxNP, PMW with a hxHDP would exhibit greater IMT and lower vascular endothelial function when matched for traditional and female-specific CVD risk factors. We also hypothesized that the circulating milieu of PMW with a hxHDP would induce greater endothelial cell mitoROS compared with PMW with a hxNP. Methods: Fourteen healthy PMW with a hxHDP were identified from the Integrative Physiology of Aging Laboratory database and matched with 14 PMW with a hxNP based on traditional CVD risk factors and gynecological/obstetric history. PMW were ≥55 years of age and postmenopausal based on self-reported amenorrhea ≥1 year and/or circulating follicle-stimulating hormone >40 mIU/mL. PMW were free from overt CVD and not currently using hormone therapy. Carotid IMT was assessed by B-mode ultrasonography at the common carotid artery (n=11–12/group). Vascular endothelial function was assessed by brachial artery flow-mediated dilation (FMDBA) expressed as a percent change in diameter from baseline (n=14/group). Human aortic endothelial cells (HAECs) were exposed to 10% PMW serum for 2 hours (n=12/group); basal mitoROS bioactivity was quantified by fluorescent microscopy. Data are presented as mean±SEM. Results: PMW with a hxHDP were on average 33±3 years after their hypertensive pregnancy and PMW with a hxNP were on average 33±2 years after their last pregnancy. Importantly, PMW with a hxHDP and a hxNP were well matched for traditional and female-specific CVD risk factors including chronological age (hxHDP, 65±1 years; hxNP, 66±1 years; p=0.53), systolic blood pressure (hxHDP, 126±2 mmHg; hxNP, 124±4 mmHg; p=0.63), and diastolic blood pressure (hxHDP, 75±1 mmHg; hxNP, 74±2 mmHg; p=0.55). Carotid IMT was 14% greater (p< 0.05) in PMW with a hxHDP (0.65±0.03 mm) compared with PMW with a hxNP (0.57±0.02 mm). FMDBA was 31% lower (p< 0.05) in PMW with a hxHDP (4.6±0.8%) compared with PMW with a hxNP (6.7±0.5%). MitoROS bioactivity in HAECs exposed to serum from PMW with a hxHDP was 14% greater (p< 0.05; 1.14±0.05 AU) than with serum from PMW with a hxNP (1.0±0.04 AU). Conclusions: PMW with a hxHDP demonstrate greater carotid IMT and lower vascular endothelial function compared with PMW with a hxNP. A less favorable circulating milieu contributes to greater endothelial cell mitoROS bioactivity in PMW with a hxHDP. Collectively, these findings provide insight into potential physiological and biological mechanisms contributing to elevated CVD risk in PMW with a prior HDP. Funding: F31AG087709 (SD), F32HL167552 (KOM), R01AG071506 and R01AG066730 (DRS), 23CDA1056582 (MJR). This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.