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Background: Persons living with the human immunodeficiency virus (PLHIV) and treated with anti-retroviral therapy such as emtricitabine and tenofovir disoproxil fumarate (Truvada, TVD) have increased cardiovascular risk but the mehcamisms and management are unclear. Since we found that PLHIV treated with antiretroviral drugs including TVD had significantly (P<0.05) decreased adiponectin in plasma (3.3±0.3 vs 4.5±0.5 μg · mL-1) and in perivascular adipose tissue (14±1 vs 22±2 μg·mg protein-1 ·mL-1), we tested the hypothesis that impaired adiponectin signaling with TVD causes microvascular dysfunction. Methods: CB57Bl/6 mice (n=6-8/ group) were administered vehicle (Veh), TVD (30 mg/kg/day), AdipoRon (ADR; adiponectin receptor agonist; 50 ug/kg/day) or both orally for 28 days. Mesenteric resistance arterioles were studied on isometric myographs and microvascular nitric oxide (NO) and reactive oxygen species (ROS) by RatioMaster. Results: TVD significantly (P<0.05) increased malondialdehyde in serum (50±5 vs 17±2 μM) and in urine (59±15 vs 7±3 μM), urine albumin/creatinine ratio (0.9±0.1 vs 0.04±0.0), microvascular contractions to U-46,619 (98± vs 88±3%; P<0.05) and endothelin-1 (83± vs 69±3%), cellular ROS (DHE: 0.29±0.03 vs 0.15±0.04 unit) and mitochondrial ROS (mitotempo: 0.25±0.04 vs 0.12±0.03 unit) and reduced endothelium-dependent relaxation (48± vs 81±3%) and NO (0.28±0.03 vs 0.42±0.07 units). ADR alone did not alter these measurements but significantly (P<0.05) prevented all of these effects of TVD. Conclusions: Activation of adiponectin receptors prevents the systemic and microvascular oxidative stress, microvascular endothelial dysfunction and NO deficiency and enhanced contractility caused by one month of TVD. Therefore, AdipoRon may mitigate the excess cardiovascular disease of PLHIV who are receiving Truvada. NIH National Heart, Lung, and Blood Institute, NIH 5RO1-HL134511 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.