Extracellular vesicle TGF-β1 is linked to cardiopulmonary dysfunction in HIV.

Extracellular vesicles (EVs) have emerged as important mediators in cell-cell communication, however; their relevance in pulmonary hypertension (PH) secondary to HIV infection is yet to be explored. Considering that circulating monocytes are the source of increased perivascular macrophages surrounding the remodeled vessels in PH, this study aimed to identify the role of circulating small EVs and EVs released by HIV-infected human monocyte-derived macrophages in the development of PH. We report significantly higher numbers of plasma-derived EVs carrying higher levels of TGF-β1 in HIV infected individuals with PH compared to without PH. Importantly, levels of these TGF-β1-loaded plasma-derived EVs correlated with pulmonary arterial systolic pressures and CD4 counts, but not with diffusion capacity for carbon monoxide (DLCO) or viral load. Correspondingly, enhanced TGF-β1-dependent pulmonary endothelial injury and smooth muscle hyperplasia were observed. HIV-1-infection of monocyte-derived macrophages in the presence of cocaine resulted in an increased number of TGF-β1 high-EVs and; intravenous injection of these EVs in rats led to increased right ventricle systolic pressure accompanied by myocardial injury and increased levels of serum endothelin-1, TNF-α, and cardiac Troponin-I. Conversely, pretreatment of rats with TGF-β-Receptor 1 inhibitor prevented these EV-mediated changes. Findings define the ability of macrophage-derived small EVs to cause pulmonary vascular modeling and PH via modulation of TGF-β signaling and suggest clinical implications of circulating TGF-β high-EVs as a potential biomarker of HIV-PH.