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. Author manuscript; available in PMC: 2026 Oct 14.
Published before final editing as: Pregnancy Hypertens. 2026 Sep 23;46:101526. doi: 10.1016/j.preghy.2026.101526

Prenatal Aspirin Use Is Associated With Preserved Vascular Endothelial Function Measured After Pregnancy in Women With a History of Preeclampsia

Ruda Lee 1, Kelsey S Schwartz 1,2, Mark K Santillan 3, Donna A Santillan 3, Gary L Pierce 1,2, Anna E Stanhewicz 1
PMCID: PMC13660965  NIHMSID: NIHMS2213024  PMID: 42777381

Abstract

Vascular endothelial dysfunction is a pathophysiological feature of preeclampsia that persists after pregnancy and likely contributes to increased cardiovascular disease (CVD) risk later in life among women with a history of preeclampsia (hxPE). Low-dose aspirin (LDA; 75-150mg/day) is recommended for pregnant women at high risk of preeclampsia and may help stabilize endothelial function. We hypothesized that endothelial function would be preserved in women with hxPE who used LDA during pregnancy. Three groups were studied: women with a history of uncomplicated pregnancy (hxHC; n=10; 35±6 years), women with hxPE who used prenatal LDA (hxPE+LDA; n=10, 34±6 years), and women with hxPE who did not use prenatal LDA (hxPE−LDA; n=10; 34±5 years). Macrovascular endothelial function was evaluated using brachial artery flow-mediated dilation (FMD). Cutaneous vascular conductance (CVC) responses to acetylcholine alone or with nitric oxide (NO) synthase inhibition were measured to assess microvascular endothelium-dependent and NO-dependent vasodilation. CVC responses to endothelin-1 (ET-1) were used to assess microvascular vasoconstriction. hxPE+LDA did not differ from hxHC across any macrovascular and microvascular function measures (all P>0.09). In contrast, hxPE−LDA exhibited lower absolute FMD and peak shear rate-normalized FMD compared with hxHC (all P<0.04). Reduced microvascular endothelium-dependent dilation and increased ET-1-mediated vasoconstriction were observed in hxPE−LDA compared with hxHC (all P≤0.031). These data suggest that prenatal LDA use is associated with preserved endothelial function and normalized ET-1-mediated vasoconstriction after pregnancy in women with hxPE, representing an early opportunity to mitigate progression toward CVD in these high-risk women.

INTRODUCTION

Preeclampsia is a hypertensive multiorgan disorder (1) that affects 2–8% of pregnancies worldwide (2). Although symptoms typically resolve following delivery, women with a history of preeclampsia (hxPE) have a 4-fold higher risk of developing cardiovascular disease (CVD) (3, 4), the leading cause of death among women globally (5, 6).

Vascular endothelial dysfunction is a potent predictor of CVD (7) and a likely pathophysiological mechanism contributing to accelerated CVD progression in women with hxPE (8). Maternal endothelial dysfunction is present during preeclampsia and persists postpartum (9), and otherwise healthy women with hxPE have reduced endothelium- and nitric oxide (NO)-dependent dilation (10, 11). We have previously demonstrated that this endothelial dysfunction is mediated, in part, by increased vascular sensitivity to endothelin-1 (ET-1) (12); partly attributable to an imbalance in endothelin receptor type A (ETAR) and type B (ETBR) responses (12, 13). Given that endothelial dysfunction is an early and modifiable mechanism contributing to CVD progression (14), precise characterization of the vascular phenotype associated with hxPE will better inform chronic CVD prevention and treatment in these women.

Low-dose aspirin (LDA; 75–150mg/daily) starting at 12 weeks of gestation is an effective therapy for delaying preeclampsia onset and reducing preeclampsia severity in women at high risk (15-17). Although the exact mechanism(s) by which LDA exerts these positive effects are unclear, reduced production of thromboxane, attenuated inflammation, and reduced platelet aggregation are all plausible mechanisms (18-20). Outside of preeclampsia, LDA has demonstrated beneficial effects on vascular endothelial function (21) by enhancing NO bioavailability and attenuating ET-1-mediated vasoconstriction (22, 23) in clinical populations. However, it is unknown whether LDA during pregnancy modulates vascular function after a pregnancy complicated by preeclampsia.

We sought to investigate the effects of LDA use during pregnancy on endothelium-dependent dilation and ET-1-mediated constriction after pregnancy in otherwise healthy women with hxPE. We hypothesized that macrovascular and microvascular endothelium-dependent dilation in women with hxPE who used LDA (hxPE+LDA) would not differ from women with a history of healthy pregnancy (hxHC), whereas women with hxPE who did not use LDA (hxPE−LDA) would exhibit lower endothelium-dependent dilation compared with hxHC. We further hypothesized that ET-1-mediated microvascular constriction would not differ between hxHC and hxPE+LDA, and that hxPE−LDA would have greater ET-1-mediated constriction, in part from reduced ETBR-mediated dilation and increased ETAR-mediated constriction, compared with hxHC.

METHODS

Ethical Approval

All protocols were approved by the University of Iowa Institutional Review Board (IRB# 202203433 and #202303799) and the U.S. Food and Drug Administration (IND# 124,294). Written and verbal consent were obtained from all participants prior to study enrollment.

Participants

Thirty healthy women aged 19–45 years ≤5 years postpartum were enrolled: 10 women with hxPE who used LDA during pregnancy (hxPE+LDA), 10 who did not use LDA during pregnancy (hxPE−LDA), and 10 women with a history of uncomplicated pregnancy who were not treated with LDA (hxHC). The diagnosis and severity of preeclampsia were determined by an obstetrician (24). Prenatal aspirin use was self-reported and verified through electronic medical records. Exclusion criteria included current pregnancy, tobacco/e-cigarette use, history of cardiovascular or metabolic diseases, and/or current use of anti-hypertensive or cholesterol-lowering medications.

Study Procedures

Participant screening included a physical exam, urine pregnancy test, and fasting blood chemistry. Eligible participants completed two visits to assess macrovascular and microvascular function. Participants were asked to abstain from caffeine for 12 hours, alcohol consumption for 24 hours, and vigorous exercise for 24 hours prior to both study visits. Physical activity, sleep quality, and perceived stress were assessed via validated self-report questionnaires (25-27).

Macrovascular Endothelial Function

Brachial artery flow-mediated dilation (FMD) in response to reactive hyperemia was measured using a high-resolution ultrasonography (Logiq E9; GE Healthcare, Milwaukee, WI) with a 9 MHz linear transducer. Participants rested in the supine position with the abducted left arm for ~10 minutes. Baseline images were recorded for 30 seconds. A pressure cuff (E20 & AG101; D.E. Hokanson, Bellevue, WA) on the left forearm was inflated to 250mmHg for 5 minutes and then rapidly deflated. Brachial artery images were continuously recorded for 2 minutes to capture the hyperemic response.

Microvascular Endothelial Function

Intradermal microdialysis was used to assess cutaneous microvascular endothelial function and ET-1-mediated responses to locally delivered pharmacological agents, as previously described (11). Five intradermal microdialysis fibers (CMA 31 Linear Microdialysis Probe; Harvard Apparatus, Holliston, MA) were placed ~5cm apart (28) in the left ventral forearm. Laser-Doppler probes (moorVMS-LDF2; Moor instruments, Wilmington, DE) secured in local heaters (moorVMS-HEAT; Moor instruments, Wilmington, DE) were placed over each fiber to obtain laser-Doppler flux (LDF). Brachial blood pressures (SureSigns VS2+; Philips Healthcare, Andover, MA) were measured on the right arm every 5 minutes. Following hyperemia-resolution (~60 minutes), baseline measurements were collected (~20 minutes) at thermoneutral (33°C) prior to the dose-response protocols. All solutions were perfused at 2μL/min (Bee Hive controller and Baby Bee microinfusion pumps; Bioanalytical Systems, West Lafayette, IN).

Acetylcholine (ACh) dose-response:

Two sites were selected to receive ACh (United States Pharmacopeia, Rockville, MD) in either lactated Ringer’s (control) or 15mM L-NAME (NG-nitro-L-arginine methyl ester; Calbiochem, EDM Millipore, Billerica, MA). Graded doses of ACh (10−10–10−1M) were perfused sequentially for 5 minutes at each concentration. Following the ACh dose-response, site-specific maximum dilation was determined [~20 minutes; 28mM sodium nitroprusside (United States Pharmacopeial, Rockville, MD) and local heat(43°C)].

ET-1 dose-response:

Three sites were randomly assigned for the local delivery of Ringer’s (control), 300nM BQ-788 (ETBR antagonist; Sigma, St. Louis, MO), or 500nM BQ-123 (ETAR antagonist; Sigma, St. Louis, MO). Ascending concentrations of ET-1 (10−20–10−8M) were perfused sequentially for 10 minutes at each concentration.

Data and Statistical Analysis

Macrovascular endothelial function data were analyzed offline using edge-detection wall tracking software (Vascular Analysis Tools; Medical Imaging Applications LLC, Coralville, IA). FMD was expressed as absolute change (peak diameter–baseline diameter), indicating the direct physiological increase in arterial diameter following the shear rate stimulus, and relative change [((peak diameter–baseline diameter)/baseline diameter)×100], reflecting the proportional change in diameter after accounting for baseline diameter and thereby facilitating comparison across individuals with varying baseline diameters. Shear rate area under the curve (SRAUC) was quantified from cuff deflation to peak diameter and represents the cumulative shear rate stimulus, while SRpeak was defined as the highest 4-cycle mean and reflects the maximal shear stimulus (29). Both SRAUC and SRpeak were used to characterize the magnitude of the shear rate stimulate associated the FMD response (30). Additionally, allometrically scaled FMD, a statistical correction method (31), was used to minimize potential effects of baseline diameter.

Microvascular endothelial function data were recorded and stored at 40Hz for offline analysis (PowerLab and LabChart; ADInstruments, Sydney, Australia). Absolute cutaneous vascular conductance was calculated (CVC=LDF/mean arterial pressure) and normalized to either maximum (%max) for ACh sites or baseline (%base) for ET-1 sites. Total ET-1-mediated responses were calculated as the area under the curve across all ET-1 doses.

A sample size of 10 participants per group was determined a priori based on previous (12) and preliminary data (power=0.80, α=0.05). Normality of continuous variables was assessed using the Shapiro-Wilk test and visual inspection of normality plots. Gestational age at preeclampsia diagnosis was compared between groups via unpaired Student’s t-test. Categorical variables were analyzed using chi-square or Fisher’s exact tests, as appropriate. Group differences in participants’ characteristics, FMD, SR, and peak CVC were assessed using one-way ANOVA. Repeated-measures ANOVA (group×dose×site) was used to analyze CVC data. Tukey’s post hoc tests were applied when significant main effects were found. Statistical analyses were conducted using SAS 9.4 (SAS Institute Inc., Cary, NC) and IBM SPSS Statistics 29.0 (IBM Corp., Chicago, IL). Statistical significance was set at P<0.05.

RESULTS

Participant Characteristics

Participant characteristics are presented in Table 1. There were no group differences in age, body mass index, physical activity, and parity (all P≥0.57). Systolic blood pressure was higher in hxPE−LDA than in hxHC (P=0.01), although mean values were within the normal range in all groups (32). hxPE+LDA exhibited higher Pittsburgh Sleep Quality Index (PSQI) scores, indicating lower sleep quality, compared with hxPE−LDA (P=0.02), and had shorter time postpartum compared with hxHC (P<0.01). PSQI scores were significantly correlated with time postpartum, such that shorter time postpartum was associated with lower sleep quality (r=−0.41, P=0.02). However, time postpartum was not associated with the primary vascular outcomes (all P>0.49). Additionally, gestational age at delivery was lower in hxPE−LDA (P=0.02), but not in hxPE+LDA (P=0.28), compared with hxHC.

Table 1.

Participant characteristics

Clinical Characteristics hxHC
(n = 10)		 hxPE−LDA
(n = 10)		 hxPE+LDA
(n = 10)		 P value
Age (years) 35 ± 6 34 ± 5 34 ± 6 0.83
Height (cm) 164.8 ± 7.8 165.9 ± 6.1 163.8 ± 6.4 0.80
Weight (kg) 74.1 ± 8.6 78.3 ± 15.6 80.8 ± 13.7 0.51
BMI (kg/m2) 27.6 ± 5.1 28.5 ± 5.9 30.1 ± 5.1 0.57
SBP (mmHg) 105 ± 7 115 ± 9* 113 ± 5 0.01
DBP (mmHg) 66 ± 6 71 ± 9 71 ± 7 0.26
MAP (mmHg) 79 ± 6 86 ± 9 85 ± 6 0.08
Total cholesterol (mg/dL) 175 ± 35 186 ± 27 172 ± 30 0.57
HDL (mg/dL) 58 ± 20 55 ± 9 57 ± 16 0.94
LDL (mg/dL) 103 ± 27 113 ± 23 99 ± 28 0.47
Fasting glucose (mg/dL) 85.9 ± 9.6 80.4 ± 5.8 82.6 ± 5.0 0.24
HbA1c (%) 5.2 ± 0.3 5.2 ± 0.2 5.1 ± 0.3 0.60
Lifestyle Characteristics
MVPA (MET-hours/weeks) 108.7 ± 73.8 95.7 ± 43.9 117.4 ± 33.9 0.66
Total PA (MET-hours/weeks) 303.8 ± 104.6 302.3 ± 87.5 288.6 ± 61.9 0.91
PSQI global score 5 ± 3 4 ± 1 8 ± 3† 0.02
Perceived stress scale score 12 ± 5 11 ± 6 18 ± 7 0.07
Race [n (%)]
White 8 (80) 7 (70) 10 (10) 0.34
Black or African American 2 (20) 2 (20) 0 (0)
More than one race 0 (0) 1 (10) 0 (0)
Ethnicity [n (%)]
Not Hispanic or Latino 9 (90) 8 (80) 9 (90) 0.75
Hispanic or Latino 1 (10) 2 (20) 1 (10)
Pregnancy History
Time postpartum (month) 37 ± 16 28 ± 16 15 ± 9* 0.01
Parity (number) 2 ± 1 2 ± 1 2 ± 1 1.00
GA at delivery (weeks) 39 ± 1 35 ± 3* 37 ± 2 0.01
GA at diagnosis (weeks) 35 ± 4 36 ± 3 0.55
Early-onset PE [n (%)] 3 (30) 1 (10) 0.58
PE with severe symptoms [n/N (%)] 7/8 (87.5) 5/8 (62.5) 0.57
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Data are means ± SD. hxHC, women with a history of healthy pregnancy; hxPE−LDA, women with a history of preeclampsia not treated with prenatal low-dose aspirin; hxPE+LDA, women with a history of preeclampsia treated with prenatal low-dose aspirin; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; MAP, mean arterial pressure; HDL, high-density lipoprotein; LDL, low-density lipoprotein; HbA1c, glycohemoglobin; MVPA, moderate to vigorous physical activity; PA, physical activity; PSQI, Pittsburgh Sleep Quality Index; GA, gestational age; PE, preeclampsia. Information on severe symptoms of preeclampsia was available through medical record review for 8 participants in each hxPE group. Early-onset PE was defined as gestational age at diagnosis <34 weeks. P values were calculated using one-way ANOVA for comparisons among groups. Categorical variables, including race, ethnicity, early-onset preeclampsia, and preeclampsia with severe features, were analyzed using chi-square or Fisher’s exact tests. GA at preeclampsia diagnosis was compared between hxPE−LDA and hxPE+LDA groups using an unpaired Student’s t-test.

*

P<0.05 vs. HC

†

P<0.05 vs hxPE−LDA.

Macrovascular Endothelial Function

Brachial artery diameter, shear rate, and FMD are presented in Table 2 and Figure 1. Baseline diameter, peak diameter, and time to peak were not different among groups (all P≥0.28; Table 2). hxPE−LDA had higher SRAUC compared with hxHC and hxPE+LDA (both P=0.04), and higher SRpeak compared with hxPE+LDA (P=0.02). Absolute FMD was significantly lower in hxPE−LDA than hxHC (P=0.015). When normalized to shear rate, absolute FMD/SRpeak remained significantly lower in hxPE−LDA compared with both hxHC and hxPE+LDA (both P≤0.036), while the group difference was no longer observed in absolute FMD/SRAUC (P=0.10; Table 2). There were no significant group differences in relative FMD and FMD/SRAUC (both P≥0.056; Figure 1A and 1B). Consistent with the findings for absolute FMD, relative FMD/SRpeak was lower in hxPE−LDA compared with hxHC and hxPE+LDA (both P≤0.031; Figure 1C). Additionally, scaled FMD in hxPE−LDA was lower compared with hxHC (P=0.03; Figure 1D). hxPE+LDA did not differ from hxHC in any comparison of macrovascular endothelial function measures (all P≥0.41; Table 2 and Figure 1).

Table 2.

Brachial artery diameter, shear rate, and absolute flow-mediated dilation variables

hxHC
(n = 9)		 hxPE−LDA
(n = 10)		 hxPE+LDA
(n = 10)		 P value
Baseline diameter (mm) 3.2 ± 0.6 3.1 ± 0.3 3.3 ± 0.3 0.61
Peak diameter (mm) 3.4 ± 0.6 3.3 ± 0.3 3.5 ± 0.3 0.28
TTP (s) 46.0 ± 10.0 55.8 ± 16.3 49.4 ± 12.4 0.28
SRAUC (s−1) 50100 ± 16748 70122 ± 15227*† 50575 ± 12072 0.02
SRpeak (s−1) 1565 ± 290 2001 ± 432† 1450 ± 397 0.02
Absolute FMD (mm) 0.24 ± 0.03 0.19 ± 0.05* 0.22 ± 0.04 0.02
Absolute FMD/SRAUC (mm·s·10−5) 0.058 ± 0.038 0.030 ± 0.008 0.047 ± 0.017 0.10
Absolute FMD/SRpeak (mm·s·10−4) 0.16 ± 0.05 0.10 ± 0.02*† 0.17 ± 0.05 0.02
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Data are means ± SD. hxHC, women with a history of healthy pregnancy; hxPE−LDA, women with a history of preeclampsia not treated with prenatal low-dose aspirin; hxPE+LDA, women with a history of preeclampsia treated with prenatal low-dose aspirin; TTP, time to peak; SR, shear rate; AUC, area under the curve; FMD, flow-mediated dilation. Shear rate-normalized absolute FMD included hxHC (n = 8), hxPE−LDA (n = 7), and hxPE+LDA (n = 9). P values were calculated using one-way ANOVA for comparisons among groups.

*

P<0.05 vs. HC

†

P<0.05 vs hxPE+LDA.

Figure 1.

Figure 1.

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Relative flow-mediated dilation (FMD; 1A, %), shear rate area under the curve normalized relative FMD (1B, %·s·10−3), peak shear rate normalized relative FMD (1C, %·s·10−3), and scaled FMD (1D, %). Relative and scaled FMD (A and D) included hxHC (n=9), hxPE−LDA (n=10), hxPE+LDA (n=10). Shear rate-normalized FMD (B and C) included hxHC (n=8), hxPE−LDA (n=7), hxPE+LDA (n=9). hxHC, women with a history of healthy pregnancy; hxPE−LDA, women with a history of preeclampsia not treated with prenatal low dose aspirin; hxPE+LDA, women with a history of preeclampsia treated with prenatal low dose aspirin.

Microvascular Endothelial Function – Cutaneous vasodilator responses

Microvascular endothelium-dependent vasodilation responses are presented in Figure 2. At the control site, hxPE−LDA had attenuated endothelium-dependent responses to ACh doses 10−3 and 10−2 compared with hxHC (both P≤0.03; Figure 2A). Vasodilatory responses were not different with NOS-inhibition (group×dose interaction, P=0.91; Figure 2C). Across all groups, responses in the NOS-inhibited site were blunted compared with the control site (P>0.001; Figure 2A and 2C). Peak CVC responses at the control site were reduced in hxPE−LDA compared with hxHC and hxPE+LDA (both P≤0.018; Figure 2B), whereas peak CVC responses at the NOS-inhibited site did not differ between groups (main effect of group; P=0.46; Figure 2D). ACh-mediated responses were not different between hxPE+LDA and hxHC (all P≥0.09; Figure 2A and 2B). Further, there were no group differences in baseline or maximal CVC (both P≥0.62; Table 3).

Figure 2.

Figure 2.

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Cutaneous vasodilation responses (cutaneous vascular conductance, CVC, %max) to acetylcholine (ACh) at control (lactated Ringer’s) (2A) and nitric oxide (NO) synthase (NOS)-inhibited sites (2C) in hxHC (n=10), hxPE−LDA (n=10), and hxPE+LDA (n=10). Peak CVC in control site (2B, %max) and in NOS-inhibited sites (2D, %max). hxHC, women with a history of healthy pregnancy; hxPE−LDA, women with a history of preeclampsia not treated with prenatal low dose aspirin; hxPE+LDA, women with a history of preeclampsia treated with prenatal low dose aspirin. *P<0.05 vs. hxHC, †P<0.05 vs. control site within group.

Table 3.

Baseline and maximal absolute cutaneous vascular conductance (flux·mmHg−1)

Microdialysis Site hxHC
(n = 10)		 hxPE−LDA
(n = 10)		 hxPE+LDA
(n = 10)
Acetylcholine + Lactated Ringer’s
 Baseline 0.2 ± 0.1 0.2 ± 0.1 0.2 ± 0.1
 Maximum 1.6 ± 0.7 2.0 ± 1.3 2.1 ± 1.1
Acetylcholine + L-NAME
 Baseline 0.1 ± 0.1 0.1 ± 0.1 0.1 ± 0.0
 Maximum 1.7 ± 0.7 2.1 ± 1.6 1.5 ± 0.6
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Data are means ± SD. hxHC, women with a history of healthy pregnancy; hxPE−LDA, women with a history of preeclampsia not treated with prenatal low-dose aspirin; hxPE+LDA, women with a history of preeclampsia treated with prenatal low-dose aspirin; L-NAME, NG-nitro-L-arginine methyl ester. Baseline cutaneous vascular conductance was higher at the acetylcholine (ACh) control site compared with the ACh + L-NAME site (main effect of drug by two-way repeated measures ANOVA, P<0.01).

Microvascular Function – Cutaneous vasoconstrictor responses

Cutaneous vascular responses to ET-1 are presented in Figure 3. Within-group differences by local treatment during the ET-1 dose response are presented in panels A–C. Between group differences within each site treatment are shown as total ET-1-mediated vascular responses in panels D–F. hxPE−LDA had exaggerated ET-1-mediated vasoconstriction compared with hxHC (P<0.001), but no differences in ET-1-mediated constriction were observed between hxPE+LDA and hxHC or hxPE+LDA and hxPE−LDA (both P>0.05; Figure 3A-C). Acute ETBR inhibition with BQ-788 increased ET-1-mediated constriction in hxHC (P<0.01; Figure 3A) but had no effect in either hxPE group (both P>0.05; Figure 3B and 3C). Local ETAR blockade with BQ-123 prevented ET-1-medated constriction in all groups (all P<0.001 vs. control site within group). hxPE−LDA had greater ET-1-mediated vasoconstriction compared with hxHC and hxPE+LDA (both P<0.01; Figure 3D). No group differences were observed in total ET-1-mediated responses following local ETBR or ETAR inhibition (all P>0.05; Figure 3E and 3F).

Figure 3.

Figure 3.

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Cutaneous vasoconstriction responses (cutaneous vascular conductance, CVC, %base) to endothelin-1 (ET-1) at control (lactated Ringer’s), ETBR inhibited (BQ-788), and ETAR inhibited (BQ-123) microdialysis sites in hxHC (n=9; 3A), hxPE−LDA (n=10; 3B), and hxPE+LDA (n=9; 3C). Total ET-1-mediated responses are presented as area under the curve (arbitrary units, a.u.) for control (3D), ETBR inhibited (3E), and ETAR inhibited (3F) sites. hxHC, women with a history of healthy pregnancy; hxPE−LDA, women with a history of preeclampsia not treated with prenatal low dose aspirin; hxPE+LDA, women with a history of preeclampsia treated with prenatal low dose aspirin. *P<0.001 vs. hxHC control site, ‡P<0.001 BQ-788 vs. control within group, #P<0.001 BQ-123 vs. control within group.

DISCUSSION

The primary finding of the present study is that endothelial function in both macrovascular and microvascular beds is preserved in women with hxPE who used LDA during pregnancy, such that endothelial function in hxPE+LDA was comparable to that of hxHC. In contrast, hxPE−LDA exhibited endothelial dysfunction, including lower absolute FMD, SRpeak-normalized absolute and relative FMD, scaled FMD, and attenuated endothelium-dependent responses to ACh compared with hxHC. Furthermore, cutaneous vasoconstriction responses to ET-1 were not different between hxPE+LDA and hxHC, whereas hxPE−LDA showed greater ET-1-mediated vasoconstriction compared with hxHC and greater AUC values in response to ET-1 than both hxHC and hxPE+LDA. Taken together, these findings indicate that prenatal LDA use impact maternal vascular function following preeclampsia and suggest that prenatal LDA therapy may preserve endothelial function and attenuate ET-1-mediated constriction assessed after pregnancy in women who have had preeclampsia.

Vascular endothelial dysfunction is widely recognized as a key pathophysiological feature of preeclampsia (8, 33). Despite the resolution of the clinical symptoms of preeclampsia after pregnancy, we and others have demonstrated that women with hxPE have attenuated endothelial function (11, 34). This persistent endothelial dysfunction is a likely driving increased incidence of future CVD in women with hxPE (4). As such, a key question is whether interventions can modify or prevent endothelial dysfunction observed after preeclampsia, with the long-term goal of better understanding and treating this dysfunction before it progresses to CVD. LDA therapy during pregnancy is effective in delaying the onset and reducing the severity of preeclampsia in high-risk patients and has gained more widespread clinical use in the past decade (35). However, whether prenatal aspirin use mitigates persistent endothelial dysfunction observed after pregnancy in women with hxPE has remained unclear.

LDA administration is associated with improvements in endothelial function in populations with overt CVD (21, 23). Aside from its antithrombotic effect, LDA has pleiotropic vascular effects, including increased NO bioavailability, attenuated inflammation, and reduced oxidative stress (19, 20). Specific to pregnancy, prenatal aspirin use has been associated with improved uterine artery pulsatility indices (15, 36) and improved relative FMD in pregnant women at high risk of preeclampsia (37). Extending these findings, the present study demonstrated that prenatal LDA use is associated with preserved maternal endothelial function after pregnancy in women with hxPE. Macrovascular endothelial function, assessed by FMD, was preserved in hxPE+LDA, but reduced in hxPE−LDA compared with hxHC. Notably, despite a significantly higher shear rate in hxPE−LDA, FMD normalized to SRpeak was still lower compared with hxHC and hxPE+LDA, suggesting that prenatal LDA may preserve endothelial sensitivity to shear. Consistent with our macrovascular findings, we found that microvascular endothelial function assessed by cutaneous vasodilation responses to ACh was also preserved in hxPE+LDA, but reduced in hxPE−LDA, as reflected in both the dose-response and peak CVC responses. Notably, there were no group differences observed with NOS-inhibition, indicating similar NO-independent vasodilation among groups. Thus, the attenuated ACh-mediated responses observed in hxPE−LDA are likely mediated, in part, by reduced NO-dependent vasodilation. This observation is unlikely to reflect a persistent pharmacological effect of aspirin itself. Rather, prenatal LDA may have attenuated declines in systemic vascular function associated preeclampsia through its pleiotropic vascular effect during pregnancy, potentially contributing to better preservation of vascular function during pregnancy and reduced residual dysfunction in the years following delivery (38, 39). Together, these findings support the interpretation that prenatal LDA use mitigates persistent endothelial dysfunction, in part via NO-dependent mechanisms, across both macrovascular and microvascular beds in women with hxPE.

Exaggerated vasoconstrictor sensitivity to ET-1 contributes to maternal vascular dysfunction during preeclampsia, and persists after pregnancy (40). Preclinical studies have shown increased vascular responses to ET-1 during preeclamptic pregnancy (41, 42), and in human studies, elevated plasma ET-1 concentrations have been observed in preeclamptic women compared with healthy pregnant women (13, 43). We have previously shown augmented microvascular vasoconstrictor responses to ET-1 in women with hxPE compared to women with a history of healthy pregnancy (12). Furthermore, we have demonstrated that blocking this exaggerated ET-1-mediated constriction increases endothelium- and NO-dependent dilation in women with hxPE (12). Given that ET-1-mediated vasoconstriction involves cyclooxygenase-derived vasoconstrictor pathways, including thromboxane A2 (44), inhibition of this pathway by LDA may attenuate ET-1-mediated vasoconstriction during pregnancy and following delivery. Our findings demonstrated that ET-1-mediated vasoconstriction was not different between hxPE+LDA and hxHC, whereas hxPE−LDA exhibited greater ET-1-mediated vasoconstriction compared with hxHC. Together, these data extend our prior findings in women with hxPE, and suggest that LDA use during preeclamptic pregnancy is associated with attenuated ET-1-mediated vasoconstriction after pregnancy in these women.

The vascular actions of ET-1 are determined by the balance between vasoconstriction via ETAR and ETBR on vascular smooth muscle and vasodilation via ETBR on the endothelium (45). In patients with CVD or high CVD risk, including hypertension, ET-1 receptor localization and signaling are shifted towards vasoconstrictor pathways (46). Similarly, animal models of preeclampsia demonstrate that increased vascular responsiveness to ET-1 during pregnancy is driven by a pathological imbalance between ETAR-mediated constriction and ETBR-mediated vasodilation (42). We have previously shown that alterations in ETBR signaling contribute to microvascular dysfunction after preeclampsia, such that ETBR-mediated dilation is reduced, and ETBR-specific blockade reduces constriction and augments endothelium-dependent dilation in women with hxPE (12). In the present study, we found that ETBR-inhibition increased ET-1-mediated vasoconstriction in hxHC but had no effect on the constriction response in either hxPE group, regardless of prenatal LDA exposure. Further, we found that ETAR blockade attenuated ET-1-mediated vasoconstriction to a similar extent in all groups. Collectively, these data suggest that prenatal LDA exposure is associated with attenuated ET-1-mediated vasoconstriction after pregnancy, despite potential impairment in ETBR-mediated buffering and in the absence of altered ETAR signaling in both groups with hxPE.

LDA used during pregnancy can delay the onset of preeclampsia and reduce the risk of severe preeclampsia (15-17). In the present study, LDA was not associated with differences in gestational age at diagnosis or the prevalence of severe features (Table 1). However, while gestational age at delivery was not different between hxPE+LDA and hxHC, hxPE−LDA delivered at a significantly earlier gestational age compared with hxHC. This finding agrees with large cohort studies demonstrating that prenatal LDA is associated with a later gestational age at delivery (47), and is clinically meaningful, as population-based data demonstrate that women with preeclampsia who deliver preterm have a higher risk of long-term CVD mortality compared with women with preeclampsia whose pregnancies reach term (48).

Study Limitations

As an observational study, this study cannot exclude the possibility that our results were mediated, in part, by pathophysiological differences in preeclampsia between hxPE+LDA and hxPE−LDA. Early-onset preeclampsia (diagnosis before 34 weeks gestation) is commonly associated with abnormal placentation, greater cardiovascular dysfunction and adverse pregnancy outcomes, whereas late-onset preeclampsia (diagnosis at or after 34 weeks gestation) is more likely associated with preexisting maternal cardiovascular and/or metabolic predisposition (49). Among participants with hxPE in the present study, the prevalence of early-onset preeclampsia and severe features did not differ between hxPE+LDA and hxPE−LDA. However, our small sample size did not allow us to further examine the role of early- vs. late-onset phenotypes or presence vs. absence of severe features in our primary outcomes. Another potential limitation is that sleep quality was lower in hxPE+LDA compared with hxPE−LDA, as reflected by higher PSQI scores, and time postpartum was shorter in hxPE+LDA compared with hxHC. In the current dataset, shorter time postpartum was associated with higher PSQI scores. However, when both PSQI score and time postpartum were included as covariates, our primary vascular outcomes remained unchanged. Thus, despite shorter time postpartum and lower sleep quality at the time of testing, hxPE+LDA demonstrated preserved endothelial function. In addition, because aspirin is recommended rather than prescribed to high-risk women during pregnancy, our study was not designed to control the timing of aspirin initiation and dosage during pregnancy, and our approach relied on participant self-report and clinical notes. Future studies are needed to examine the effect of aspirin dosing and timing during pregnancy on vascular function after pregnancy in women with hxPE.

Conclusions and Implications

Women with hxPE have persistent endothelial dysfunction, a predictor of CVD morbidity and mortality, despite the resolution of clinical symptoms after delivery. Prenatal LDA is recommended for women at high risk of preeclampsia (35). Our data demonstrate that women with hxPE+LDA, even though they still developed preeclampsia, exhibited preserved vascular endothelial function after pregnancy. Furthermore, women with hxPE+LDA did not exhibit the exaggerated ET-1-mediated vasoconstriction observed in women with hxPE−LDA. These findings suggest that prenatal LDA may mitigate persistent endothelial dysfunction after pregnancy in women with hxPE. Whether preserved vascular function in women with hxPE+LDA is associated with reduced chronic CVD risk remains unknown.

HIGHLIGHTS.

  • Women with a history of preeclampsia have impaired vascular function after pregnancy.

  • Women who took aspirin during pregnancy have preserved vascular function after preeclampsia.

  • Aspirin use during pregnancy preserved endothelium dependent responses.

  • Aspirin use during pregnancy preserved endothelin-1 sensitivity.

Acknowledgments

We sincerely appreciate the participants for contributing their time and dedication to the completion of the project. We also thank Kaila Brustkern, Claire Goebel, and Jeni Michelson for their assistance with data collection.

Funding

This project was supported by American Heart Association Career Development Award 937990 (to AES) and UM1TR004403 (The University of Iowa Clinical and Translational Science Award). GLP is supported by the Russell B. Day and Florence D. Day Chair in Liberal Arts and Sciences at the University of Iowa.

Footnotes

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Conflicts of Interest: The authors declare that there are no financial or personal conflicts of interest that could have influenced the results presented in this study.

DECLARATION OF COMPETING INTERESTS

None of the authors have competing interests to declare.

Informed consent and patient details

Written informed consent to take part in the study and to publish the article has been obtained from all participants or their legal representatives. The privacy rights of participants have been observed.

Human and biological material

This study included organ or tissue donors.

This study includes human biological material and consent was obtained by donors, or their next of kin or legal representatives, for use in this study and for publication of the article. The samples used in this research were not sourced from executed prisoners or prisoners of conscience.

Studies in Human

This study was performed in compliance with relevant laws, regulatory frameworks and guidelines where the research took place.

This study was approved by the University of Iowa Institutional Review Board.

(Approval No. 202203433)

Clinical Trials

The results of this clinical trial and any associated work have been posted in a registry.

This clinical trial was registered with number NCT05653973 (ClinicalTrials.gov).

Submission Declaration: PREGHY-D-26-00103

On behalf of all authors, I attest that:
  • The work described has not been published previously except in the form of a preprint, an abstract, a published lecture, academic thesis or registered report.
  • The article is not under consideration for publication elsewhere.
  • The article's publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out.
  • If accepted, the article will not be published elsewhere in the same form, in English or in any other language, including electronically, without the written consent of the copyright-holder.

Anna Stanhewicz, PhD

Data Availability:

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

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