Angiopoietin-1 accelerates restoration of endothelial cell barrier integrity from nanoparticle-induced leakiness

Abstract

Nanoparticles (NPs) have been widely used in biomedical field for therapeutic treatments, drug carriers, and bio-imaging agent. Recent studies have highlighted the possibility of utilizing inorganic NPs in inducing endothelial leakiness through endothelial remodeling to promote drug transport across the barrier. However, an uncontrolled and persistent leakiness could lead to promiscuous transport of molecules and cells across the barrier, highlighting the pressing need to control the timely recovery from endothelial cell leakiness. Herein, we show that angiopoietin-1 (Ang1) could promote recovery of human microvascular endothelial cells (HMVECs) from titanium dioxide nanoparticle (TiO₂ NPs)-induced endothelial leakiness. Ang1 is known as an anti-permeability growth factor which forms complexes with its receptor Tie2 at the cell-to-cell junctions. We find that the introduction of Ang1 not only accelerates the recovery of NP-induced endothelial leakiness (NanoEL) but also promotes cell rigidity by increasing tubulin acetylation, thereby remodels the endothelial cells to further mitigate the effects of NP exposure through the activation of the Akt pathway. Using in vitro metastasis model, we further show that HMVECs treated with TiO₂ NPs followed by Ang1 could reduce migration of human skin cancer A431 cells across the endothelial barrier. In summary, Ang1 plays important roles in promoting the recovery of endothelial cell leakiness and endothelial stability through a mechano-transduction pathway and shows great potential as key modulator that allows material scientist to regulate endothelial leakiness induced by NPs.

Keywords:

• Titanium dioxide nanoparticles
• angiopoietin-1
• anti-permeability
• nanoparticle-induced endothelial leakiness
• recovery

Acknowledgments

The authors would like to acknowledge NUS Graduate School for Integrative Sciences and Engineering, and Professors Giorgia Pastorin and Xie Jianping for the helpful discussions.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Funding for this work was provided by the Ministry of Education Academic Research Grants [R-148-000-217-112 and R-148-000-272-114 to HHK] and [R-279-000-418-112 to DTL].