African American women experience a disproportionate burden of hypertension and chronic kidney disease, yet their molecular underpinnings remain understudied. This study uniquely integrates transcriptomic data from 344 African American women to uncover 95 female-specific genes jointly associated with hypertension and reduced kidney function. These genes implicate immune activation, cytoskeletal remodeling, and metabolic dysregulation as key contributors to renal decline. By identifying sex-specific molecular pathways, this work advances precision medicine approaches to address kidney health disparities.

Background: Hypertension and preeclampsia are clinically distinct, yet biologically related conditions characterized by vascular dysfunction and elevated cardiovascular risk. Although genome-wide association studies (GWAS) have identified loci associated with blood pressure traits and preeclampsia, the functional mechanisms linking shared variants to gene regulation and clinical phenotypes remain unclear. Methods: We integrated GWAS summary statistics for hypertension, systolic blood pressure (SBP), diastolic blood pressure (DBP), and preeclampsia to identify shared variants (p ≤ 1×10⁻⁴). Cis-expression quantitative trait loci (eQTL) analyses were performed in whole blood using RNA-seq data from 180 African American women. Significant associations (FDR ≤ 0.05) were evaluated for replication across vascular, metabolic, and endocrine tissues in the Genotype-Tissue Expression (GTEx) project. Associations between gene expression and blood pressure traits were also assessed. Results: We identified 4,792 shared GWAS variants, of which 4,663 were tested in eQTL analyses, yielding 1,837 significant variant-gene associations across 78 genes. Replication in GTEx confirmed 645 associations involving 24 genes, many showing cross-tissue regulatory effects. Three genes (C4B, HLA-C, and HLA-DQB1) demonstrated convergent evidence across GWAS, gene regulation, and expression-trait analyses. C4B expression was positively associated with hypertension and SBP, while HLA-C showed consistent negative associations with hypertension, SBP, and DBP. HLA-DQB1 expression was specifically associated with DBP, suggesting trait-specific effects. Conclusions: These findings highlight immune-related pathways as key mediators linking hypertension and preeclampsia. Integrating genetic, transcriptomic, and phenotypic data provides a framework for identifying functionally relevant loci and advancing mechanistic insights into cardiometabolic and pregnancy-related disorders. GRAPHICAL Shared genetic variants across hypertension, blood pressure traits, and preeclampsia converge on immune regulatory genes linking gene regulation to clinical phenotypes. GWAS summary statistics for hypertension, SBP, DBP, and preeclampsia were intersected to identify 4,792 shared variants, of which 4,663 were tested in cis-eQTL analyses in whole blood from 180 African American women ( left ). Shared variants regulate immune-related genes through cis-eQTL effects, yielding 1,837 associations involving 78 genes (FDR ≤ 0.05). Three convergent genes emerged: C4B (upregulated), HLA-C (downregulated), and HLA-DQB1 (upregulated), with 645 associations involving 24 genes replicated across eight tissues in GTEx ( center ). Expression-trait analyses confirmed that C4B expression was positively associated with hypertension and SBP, HLA-C expression was negatively associated with hypertension, SBP, and DBP, and HLA-DQB1 expression was specifically associated with DBP. These genes implicate complement activation, antigen presentation, and adaptive immunity as shared mechanisms contributing to vascular dysfunction in both hypertension and preeclampsia. eQTL indicates expression quantitative trait locus; FDR, false discovery rate; GTEx, Genotype-Tissue Expression project; SBP, systolic blood pressure; DBP, diastolic blood pressure; APC, antigen-presenting cell; TCR, T-cell receptor; MHC, major histocompatibility complex.

Background: Metabolically healthy obesity (MHO) is unstable, with up to 80% of individuals progressing to metabolically abnormal obesity (MAO), yet mechanisms underlying this transition remain unclear. African Americans bear a disproportionate burden of obesity-related cardiovascular disease. Circulating extracellular vesicles (EVs) mediate inter-organ communication and may drive MAO-related vascular dysfunction. Methods: Adults of African ancestry were classified as metabolically healthy lean (MHL, n=14), MHO (n=9), or MAO (n=16). Plasma-derived EVs were characterized and their microRNA cargo profiled. Human coronary artery endothelial cells were treated with EVs from each group to assess nitric oxide signaling, oxidative stress, inflammatory activation, and mitochondrial dynamics. Results: MHO participants exhibited preserved insulin sensitivity and lower inflammation compared with MAO despite comparable adiposity. EVs from MHO carried a distinct microRNA signature enriched in miR-148a-5p, miR-181c-5p, and miR-1255a, linked to antioxidant and matrix regulatory pathways. MAO EVs were enriched in miR-3613-3p, miR-6842-3p, and miR-326, targeting inflammation and insulin resistance pathways. Compared with both MHL and MHO EVs, MAO EVs suppressed endothelial nitric oxide synthase phosphorylation and reduced nitric oxide bioavailability, with increased reactive oxygen species and ICAM-1 expression. MHO EVs induced an intermediate phenotype with disrupted mitochondrial morphology, supporting a graded continuum of endothelial stress. Conclusions: MHO represents a biologically active intermediate state. Circulating EVs from MHO individuals convey molecular signals that impair endothelial and mitochondrial function, predisposing to vascular injury and progression toward MAO. EV-associated microRNAs are mechanistic mediators and candidate biomarkers of metabolic and vascular deterioration in obesity. CLINICAL PERSPECTIVE: What Is New?: This study systematically investigated extracellular vesicles derived from metabolically healthy obese individuals to define direct vesicle effects on endothelial function using integrated omics coupled to functional outputs. Extracellular vesicles from metabolically healthy obesity convey a distinct molecular and biological signature that distinguishes lean and metabolically abnormal obesity. Metabolic health status, rather than obesity alone, drives extracellular vesicle-mediated endothelial nitric oxide signaling, oxidative stress, inflammation, and mitochondrial dynamics. What Are the Clinical Implications?: These findings explain why some individuals with obesity exhibit preserved vascular function while others develop early endothelial dysfunction. Stratifying obesity by metabolic health status improves cardiovascular risk assessment beyond body mass index alone. Targeting extracellular vesicle signaling pathways represents a novel strategy to prevent metabolically healthy individuals from progressing to metabolically abnormal obesity.

RNA- and protein-based medicines are expanding cardiovascular therapeutic options, but efficient delivery to cardiomyocytes, fibroblasts, vascular cells, and lesional immune cells remains difficult. Target selection also relies disproportionately on European-ancestry datasets, limiting causal resolution and portability. This narrative review evaluates extracellular vesicles (EVs) as carriers and active biological products for cardiovascular RNA and protein therapeutics. We distinguish EVs carrying a defined active ingredient, intrinsically bioactive EV preparations, and EV-inspired synthetic systems. We link delivery design to human multi-omics by integrating diverse-ancestry genome-wide association studies, fine-mapping, molecular quantitative trait loci, colocalization, Mendelian randomization, and single-cell or spatial transcriptomics. Hepatic targets such as PCSK9, LPA, APOC3, ANGPTL3, AGT, and TTR provide benchmarks against which EV platforms can be assessed. The strongest rationale for EVs lies in extrahepatic programs where tissue access limits otherwise compelling myocardial, fibrotic, vascular, or regenerative targets. We propose a stage-gated roadmap connecting causal evidence and cell-state specificity to modality selection, cargo loading, targeting, endosomal escape, biodistribution, human cardiac models, manufacturing, potency, and safety. We then apply the framework to worked examples (LPA, CAMK2D, COL6A3-derived endotrophin, AGER/RAGE, and VEGFA), in which fine-mapping, colocalization, Mendelian randomization, ancestry-specific evidence, and cell-state localization jointly determine the modality and the carrier, including targets for which an EV is not the appropriate choice. Cited delivery studies are graded on a four-level evidence ladder spanning tissue association, intact-cargo delivery, cytosolic release, and pharmacodynamic activity, because most cardiovascular EV reports establish only the lower levels. The cardiovascular EV studies reviewed do not establish clinical benefit or an advantage over optimized lipid nanoparticles at matched active-cargo dose in a cardiovascular disease model. Clinical translation depends on reproducible functional delivery, a defined mechanism, consistent product quality, and meaningful benefit relative to established treatments.

Background Hypertension is a major risk factor for chronic kidney disease (CKD) and disproportionately affects African American women, contributing to disparities in kidney health outcomes. The biological mechanisms connecting hypertension to reduced kidney function, particularly in understudied populations, remain poorly understood. This study leverages transcriptomic analyses to uncover shared molecular signatures associated with hypertension and kidney function, focusing on female-specific profiles. Methods The study analyzed whole-blood mRNA sequencing data from a cohort of 344 African American women, divided equally into discovery (n = 172) and validation (n = 172) datasets, along with 147 African American men. Differential expression (DE) analyses were performed to identify mRNAs associated with hypertension and kidney function (measured as eGFR). Female-specific findings were determined by comparing results between females and males. Pathway enrichment analyses were subsequently conducted to link the identified mRNAs to key biological mechanisms. Results Comparative analyses revealed unique transcriptomic profiles in females, underscoring the role of sex-specific factors in disease progression. DE analyses identified 95 female-specific genes associated with both hypertension and eGFR. Subsequent pathway enrichment analysis with the 95 genes revealed key pathways related to fibrosis, inflammation, lipid metabolism, and endothelial dysfunction. The list of 95 includes TGF-β1 and PNPLA2 implicated in fibrotic and metabolic dysregulation, and immune system players such as IL32 and TNFSF12 that amplify inflammation and kidney injury. Conclusions This study provides novel insights into the transcriptomic mechanisms underlying hypertension and kidney function in African American women. The findings emphasize the importance of addressing sex-specific and population-specific molecular mechanisms to inform precision medicine approaches and reduce health disparities hypertension-related impaired kidney function. Future research should prioritize experimental validation and longitudinal studies to further elucidate these pathways.

BACKGROUND: Hypertension and preeclampsia are clinically distinct, yet biologically related conditions characterized by vascular dysfunction and elevated cardiovascular risk. Although genome-wide association studies have identified loci associated with blood pressure traits and preeclampsia, the functional mechanisms linking shared variants to gene regulation and clinical phenotypes remain unclear. METHODS: We integrated genome-wide association study summary statistics for hypertension, systolic blood pressure, diastolic blood pressure, and preeclampsia to identify shared variants ( P ≤1×10 ⁻⁴ ). Cis -expression quantitative trait loci analyses were performed in whole blood using RNA sequencing data from 180 Black women. Significant associations (false discovery rate ≤0.05) were evaluated for replication across vascular, metabolic, and endocrine tissues in the Genotype-Tissue Expression project. Associations between gene expression and blood pressure traits were also assessed. RESULTS: We identified 4792 shared genome-wide association study variants, of which 4663 were tested in expression quantitative trait loci analyses, yielding 1837 significant variant-gene associations across 78 genes. Replication in the Genotype-Tissue Expression project confirmed 645 associations involving 24 genes, many showing cross-tissue regulatory effects. Three genes ( C4B , HLA-C , and HLA-DQB1 ) demonstrated convergent evidence across genome-wide association study, gene regulation, and expression-trait analyses. C4B expression was positively associated with hypertension and systolic blood pressure, while HLA-C showed negative associations with hypertension, systolic blood pressure, and diastolic blood pressure. HLA-DQB1 expression was specifically associated with diastolic blood pressure, suggesting trait-specific effects. CONCLUSIONS: These findings highlight immune-related pathways as key mediators linking hypertension and preeclampsia. Integrating genetic, transcriptomic, and phenotypic data provides a framework for identifying functionally relevant loci and advancing mechanistic insights into cardiometabolic and pregnancy-related disorders.