Shear stress regulation of nanoparticle uptake in vascular endothelial cells

Abstract

Nanoparticles (NPs) hold tremendous targeting potential in cardiovascular disease and regenerative medicine, and exciting clinical applications are coming into light. Vascular endothelial cells (ECs) exposure to different magnitudes and patterns of shear stress (SS) generated by blood flow could engulf NPs in the blood. However, an unclear understanding of the role of SS on NP uptake is hindering the progress in improving the targeting of NP therapies. Here, the temporal and spatial distribution of SS in vascular ECs and the effect of different SS on NP uptake in ECs are highlighted. The mechanism of SS affecting NP uptake through regulating the cellular ROS level, endothelial glycocalyx and membrane fluidity is summarized, and the molecules containing clathrin and caveolin in the engulfment process are elucidated. SS targeting NPs are expected to overcome the current bottlenecks and change the field of targeting nanomedicine. This assessment on how SS affects the cell uptake of NPs and the marginalization of NPs in blood vessels could guide future research in cell biology and vascular targeting drugs.

Keywords: caveolin; clathrin; endothelial cell; nanoparticle uptake; shear stress.

Graphical abstract

Figure 1.

SS model in vivo. (a) Carotid artery constriction model using conical silicone cast. Panel (b) is the flow velocity of (a). Reproduced with permission from Ref. [38]. Copyright 2019, Hindawi. (c) Partial carotid arteries ligation model using sterile surgical instruments. RCA, right carotid arteries; LCA, left carotid arteries; ICA, internal carotid artery; ECA, external carotid artery; OA, occipital artery; STA, superior thyroid artery. Panel (d) is the flow velocity of (c). Reproduced with permission from Ref. [25]. Copyright 2018, Springer Nature Switzerland AG. (e) Model diagram of zebrafish. (f) Blood flow velocities in four different blood flow regions. Reproduced with permission from Ref. [37]. Copyright 2021, Elsevier B.V.

Figure 2.

Using a microfluidic system to demonstrate that LSS promotes uptake of NPs by ECs. (a) Schematic of the microfluidic system. (b) Fluorescence intensity of NP uptake by ECs at different time points with different flow rates. Reproduced with permission from Ref. [45]. Copyright 2020, WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Figure 3.

OSS promotes the uptake of RBCEVs by ECs in carotid artery ligation mice. (a) En face immunofluorescence images. OSS increased the uptake of RBCEVs by ECs. (b) Imaris 3D rendering of (a). Reproduced with permission from Ref. [37]. Copyright 2021, Elsevier B.V.

Figure 4.

Shear targeting of a thrombolytic drug in arterial thrombosis model by using shear-activated nanotherapeutics (SA-NTs). (a) SA-NTs disintegrate into single NP due to local HSS at thrombus site. (b) Accumulation of tPA-coated NPs and binding to the clot at the occlusion site progressively dissolve the obstruction. Reproduced with permission from Ref. [84]. Copyright 2021, American Association for the Advancement of Science.

Figure 5.

Oxidative stress is the regulator in LSS-induced RBCEVs uptake by ECs. (a) and (b) LSS and OSS could increase ROS generation. (c) SOD, MDA and MCP-1 levels were detected by ELISA. (d) and (e) Cellular uptake of RBCEVs was reduced after antioxidant pretreatment. Reproduced with permission from Ref. [37]. Copyright 2021, Elsevier B.V.

Figure 6.

SS regulates caveolae-associated protein expression levels. LSS upregulated the protein expression of Cav-1 compared with undisturbed shear stress (USS). Reproduced with permission [122]. Copyright 2016, Elsevier Ltd.

Figure 7.

Longitudinal distribution of NPs with different sizes and stiffness in blood vessels under different SS. (a) Soft and small NPs are more likely to be marginalized under LSS. (b) Hard and large NPs are easier to deposit on the surface of blood vessels under HSS.