Abstract 64: Microvascular Endothelial Dysfunction, Oxidative Stress and Reduced Arginine: Adma in Premenopausal Women With HIV

Abstract

Cardiovascular disease (CVD) is common in persons infected with the human immunodeficiency virus (HIV) who are receiving highly active antiretroviral therapy (HAART). Since CVD generally begins with microvascular dysfunction, we tested the hypothesis that women with HIV have microvascular endothelial dysfunction. We related this to reactive oxygen species (ROS), NOS substrate: inhibitor ratio (arginine: ADMA) and inflammation. Subcutaneous microvascular arterioles (SMAs) were isolated from gluteal skin biopsies from 11 premenopausal, virally suppressed African American HIV positive women receiving HAART but without CVD risk factors and 10 healthy matched controls in the Women’s Interagency HIV Study (WHIS). Preconstricted SMAs were mounted in a Mulvany-Halpern myograph and relaxed with graded concentrations of acetylcholine (ACh). Endothelium derived relaxation (EDR), endothelium-derived relaxation factor (EDRF; NOS-dependent relaxation), endothelium derived hyperpolarizing factor (EDHF; K + -channel dependent relaxation) and endothelium derived contracting factor (EDCF; ACh-induced contraction with relaxation pathways inhibited) were related to plasma cytokines (array) and plasma arginine: ADMA ratio (measured by capillary zone electrophoresis).Compared to controls, HIV infected subjects had reduced EDRs (50±6 vs 78±3%; P< 0.01), EDRF (27±4 vs 38±3%, P< 0.05), EDHF(18±4 vs 39±4%, P< 0.05) and decreased NO activity (0.18±0.05vs 0.69±0.17ΔUnits, P< 0.05 from DAF-FM fluorescence).They had an ACh-induced EDCF (21±2vs7±3%, P< 0.01) and increased microvascular ROS (0.14±0.04 vs 0.04±0.04 Δunits; P< 0.01 from tempo-9ACfluorescence). Plasma cytokines in HIV subjects showed enhanced inflammation and plasma arginine: ADMA concentrations were reduced (178±12 vs 203±13 μmol/ μmol; P< 0.005). In conclusion, pre-menopausal women receiving HAART with virally suppressed HIV who were free of CVD risk factors developed defective microvascular EDRF and EDHF with reduced NO and NOS substrate: inhibitor ratio. They had inflammation and their microvessels developed a new ACh-induced EDCF and enhanced ROS. These profound microvascular disturbances in apparently healthy young women may herald the development of premature CVD.