4.7 Review

Targeting Rho kinase to restore endothelial barrier function following vascular scaffold implantation

Journal

DRUG DISCOVERY TODAY
Volume 28, Issue 7, Pages -

Publisher

ELSEVIER SCI LTD
DOI: 10.1016/j.drudis.2023.103609

Keywords

endothelial barrier integrity; permeability; vascular scaffold; Rho kinase; in-stent neoatherosclerosis

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Vascular scaffold implantation causes injury to the intimal layer and disrupts the regenerated endothelial monolayer, leading to compromised barrier integrity and increased permeability. Mechanical stretching of the vascular wall triggers RhoA/Rho kinase-mediated contractility, resulting in destabilization of adherens junctions and endothelial barrier dysfunction. This review highlights the involvement of Rho GTPases in the disruption of endothelial barrier integrity following vascular scaffold implantation and the potential of targeting downstream Rho-associated protein kinases to restore endothelial barrier integrity and stability.
Vascular scaffold implantation induces injury to the intimal layer and causes discontinuity of the regenerated endothelial monolayer, compromising barrier integrity, increasing permeability, and allowing the transmigration of leukocytes and lipoproteins into the subendothelial space. Mechanical vascular wall stretching triggers Ras homolog family member A (RhoA)/Rho kinase-mediated actomyosin contractility and destabilization of adherens junctions, leading to endothelial barrier dysfunction. Assembly of intercellular adhesion and actin cytoskeletal organization of interendothelial junctions are controlled by downregulation of RhoA guanosine triphosphatase (GTPase)-mediated barrier-disruptive activity and upregulation of repressor-activator protein 1 (Rap1) and Ras-related C3 botulinum toxin substrate 1 (Rac1) GTPase-mediated cytoskeletal reorganization, leading to endothelial barrier stabiliza-tion. This review highlights the involvement of Rho GTPases in the disruption of endothelial barrier integrity following vascular scaffold implantation and the targeting of downstream Rho-associated protein kinases, which signal the network to restore endothelial barrier integrity and stability.

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