Blood Pressure and Late Pregnancy Circulating miRNAs in the MADRES Study

Abstract

Background: Circulating extracellular and vesicle particle (EVP) miRNAs have been associated with cardiovascular risk and adverse birth outcomes. Hypertensive disorders of pregnancy (HDP) increase risk for adverse birth outcomes and future cardiovascular outcomes in mothers and children and have been associated with altered maternal circulating EVP miRNA levels during pregnancy. Whether these relationships exist for elevated blood pressure (BP) in the subclinical range is unknown. We investigated associations between (1) hypertensive disorders of pregnancy and (2) maternal BP trajectories, including in the subclinical range, and circulating EVP miRNA levels during pregnancy in the MADRES (Maternal and Developmental Risks From Environmental and Social Stressors) Study (n=372).

Methods: Latent class trajectory modeling was used to identify trajectories from BP measures abstracted from medical records. The NanoString nCounter platform was used to quantify 798 miRNAs extracted from maternal blood (median gestational age: 31.6 weeks). Covariate-adjusted regression models assessed associations between each hypertensive disorders of pregnancy subtype or BP trajectory and levels of each miRNA.

Results: Three BP trajectories were identified: Low, Moderate, and High. Chronic hypertension was associated with higher levels of miR-1185-2-3p (P_{false discovery rate}<0.05), a placenta-specific miRNA linked to arterial stiffness and preterm delivery. Many placenta-expressed miRNAs previously associated with a longer gestational duration in the same cohort were lower among participants with elevated BP (P<0.05). Target genes of BP-associated EVP miRNAs were overrepresented in pathways involved in vascular inflammation, oxidative stress, endothelial dysfunction, and placental function.

Conclusions: Circulating levels of placenta-expressed EVP miRNAs previously implicated in adverse birth and cardiovascular outcomes are sensitive to elevated maternal BP during pregnancy, including in the subclinical range.

Keywords: EVP miRNAs; blood pressure; hypertension; placenta; pregnancy.

Figure 1. Systolic blood pressure trajectories.

A, Latent class trajectory modeling identified 3 SBP trajectories. Median SBP across gestation, with 95% confidence bands, is plotted by trajectory. B, Distribution of SBP measurement collection across gestation by SBP trajectory. BP indicates blood pressure; and SBP, systolic blood pressure.

Figure 2. Volcano plots showing associations between HDP subtypes or BP trajectories and each miRNA.

Volcano plots show effect estimates (x axis) and −log₁₀ P values (y axis) from robust linear regression models (primary outcomes: widely detected miRNAs) and logistic regression models (secondary outcomes: low abundance C14MC/C19MC miRNAs). (A–C) Shows the association of HDP subtypes with miRNAs of interest. (D–E) Shows the association of High and Moderate BP trajectories and these miRNAs. All analyses were adjusted for maternal age, perceived stress during pregnancy, BMI, recruitment site, and timing of enrollment. BMI indicates body mass index; BP, blood pressure; C14MC, chromosome 14 microRNA cluster; C19MC, chromosome 19 microRNA cluster; FDR, false discovery rate; and HDP, hypertensive disorders of pregnancy.

Figure 3. Venn diagrams showing overlap of miRNAs associated with HDP subtypes or BP trajectories (P<0.05).

A, Compares results for any HDP subtype and the High BP trajectory. B, Compares the High and Moderate BP trajectories. All analyses were adjusted for maternal age, perceived stress during pregnancy, BMI, recruitment site, and timing of enrollment. BMI indicates body mass index; BP, blood pressure; and HDP, hypertensive disorders of pregnancy.

Figure 4. Gene set enrichment analysis results.

Bubble plots showing the top 10 PANTHER pathways for miRNAs associated with the High BP trajectory. Bubble shade indicates the −log₁₀ (P value) from Fisher's exact tests, with darker shades signifying smaller P values. Bubble size represents the percentage of genes in each pathway. The x axis shows the odds ratio from Fisher's exact tests. Asterisks following the pathway name signify statistical significance after multiple testing correction (P _FDR<0.05). BP indicates blood pressure; IGF, insulin‐like growth factor; PANTHER, Protein Analysis Through Evolutionary Relationships; and PDGF, platelet‐derived growth factor.