Shear Stress-Induced Phenotypic Alterations in Monocytes: Exploring Rheometer Shear and ACE2 Dysregulation Effects

 Due to the increasing population of individuals with cardiovascular diseases and related comorbidities, there is a growing need for the development of synergistic therapeutics. Monocytes are implicated in a broad spectrum of diseases and can serve as a focal point for therapeutic targeting. Monocytes are members of the mononuclear phagocyte system involved in pathogen clearance and nanoparticle pharmacokinetics. Monocytes play a critical role in the development and progression of cardiovascular diseases. While studies have investigated the effect of nanoparticle modulation on monocyte uptake, their physiological responses to the shears associated with cardiovascular diseases have not been largely studied. In this thesis, we set out to determine the effect of shear on monocytes in varying physiological and mechanical models. The impact of ACE2 deficiency was explicitly investigated in the monocyte’s ability to uptake nanoparticles.

Moreover, we investigated nanoparticle uptake as a function of nanoparticle size, physiological shear stress, and monocyte ACE2 expression. Higher shear stress exposure increased nanoparticle uptake in ACE2- cells but not in wild-type cells. In addition, the shear stress and nanoparticle uptake appeared to downregulate gene expression more dramatically in ACE2- cells. Our data demonstrates that ACE2- cells exhibit different sensitivities to the same nanoparticle systems. Observing how nanoparticles can modulate monocytes in the context of disease can inform precision dosing. This work demonstrates the benefits of adding more physiologically relevant conditions to in vitro cultures to better inform disease studies, specifically in cardiovascular diseases.