Molecular Profile Of Peripheral Blood Mononuclear Cells In Hypertensive Adolescents With Target Organ Damage.

Introduction: Primary hypertension (PH) is a multifactorial disease influenced by genetic, epigenetic, and environmental factors. Despite the occurrence of PH-associated cardiovascular events in youth, the molecular mechanism(s) of target organ damage (TOD) are unknown. Objectives: (1) To identify an epigenetic signature and gene expression profiles in adolescents with low blood pressure (BP) and normal left ventricular mass (LVM) compared to those with high BP and high LVM; and (2) to determine novel gene targets and associated signaling pathways for future investigation and intervention. Methods and Results: A total of 397 participants (mean age 15.6 ±1.7 years, 59% male, 63% Caucasian) were enrolled across the distribution of BP. The average daytime ambulatory systolic BP recorded in healthy and hypertensive participants was 112 ±9.71 and 133 ±7.2 mmHg ( p<0.05 ) respectively. Clinical measures revealed higher body mass index (26.8 ±7.02 vs 29.6 ±7.88 Kg/m 2 ; p<0.05 ), and abnormal circulatory HDL (47.4 ±12.1 vs 43.4 ±11.7 mg/dL; p<0.05 ), glucose (87.8 ±7.98 vs 90.8 ±8.17 mg/dL; p<0.05 ), insulin (17.8 ±14.3 vs 23.7 ±19 μIU/dL; p<0.05 ), creatinine (0.718 ±0.13 vs 0.727 ±0.17 mg/dL; p<0.05 ), uric acid (5.4 ±1.63 vs 6.04 ±1.52 mg/dL; p<0.05 ), CRP (1.35 ±1.8 vs 1.92 ±2.14 mg/dL; p<0.05 ), and left ventricular hypertrophy (LVM/ht 2.7 ; 31.4 ±6.74 vs 33.5 ±7.15 g/m 2.7 ; p<0.05 ), and arterial stiffness (Pulse wave velocity; 4.83 ±0.69 vs 5.35 ±0.92 m/sec; p<0.05 ). Using peripheral blood mononuclear cells, mRNA-Seq, miRNA-Seq, and whole-genome DNA methylation analysis revealed master genes, and regulatory pathways related to BP regulation, tissue fibrosis and cardiovascular remodeling. Our study reveals a novel PH-associated TOD mechanism, showing angiogenesis inhibition mediated by VASH1 (Vasohibin-1) upregulation and downtrends in VASH2 (Vasohibin-2), VEGFC (Vascular endothelial growth factor C), HIF1α (Hypoxia-inducible factor 1-alpha), and IGF1 (Insulin Like Growth Factor 1). Moreover, VASH1 targeting miRNA hsa-miR-30e-5p is inversely regulated. Conclusion: Angiogenesis inhibition in the presence of common demographic and clinical intermediate-phenotypes may contribute to the development of TOD in hypertensive youth.