Rap1 Small GTPase Regulates Vascular Endothelial-Cadherin-Mediated Endothelial Cell–Cell Junctions and Vascular Permeability

Abstract

The vascular permeability of the endothelium is finely controlled by vascular endothelial (VE)-cadherinmediated endothelial cell-cell junctions. In the majority of normal adult tissues, endothelial cells in blood vessels maintain vascular permeability at a relatively low level, while in response to inflammation, they limit vascular barrier function to induce plasma leakage and extravasation of immune cells as a defense mechanism. Thus, the dynamic but also simultaneously tight regulation of vascular permeability by endothelial cells is responsible for maintaining homeostasis and, as such, impairments of its underlying mechanisms result in hyperpermeability, leading to the development and progression of various diseases including coronavirus disease 2019 (COVID-19), a newly emerging infectious disease. Recently, increasing numbers of studies have been unveiling the important role of Rap1, a small guanosine 5′-triphosphatase (GTPase) belonging to the Ras superfamily, in the regulation of vascular permeability. Rap1 enhances VE-cadherin-mediated endothelial cell-cell junctions to potentiate vascular barrier functions via dynamic reorganization of the actin cytoskeleton. Importantly, Rap1 signaling activation reportedly improves vascular barrier function in animal models of various diseases associated with vascular hyperpermeability, suggesting that Rap1 might be an ideal target for drugs intended to prevent vascular barrier dysfunction. Here, we describe recent progress in understanding the mechanisms by which Rap1 potentiates VE-cadherin-mediated endothelial cell-cell adhesions and vascular barrier function. We also discuss how alterations in Rap1 signaling are related to vascular barrier dysfunction in diseases such as acute pulmonary injury and malignancies. In addition, we examine the possibility of Rap1 signaling as a target of drugs for treating diseases associated with vascular hyperpermeability.

Differential expression profile of urinary exosomal microRNAs in patients with mesangial proliferative glomerulonephritis

“…Rap1 (also known as Krev-1) is a small GTPase belonging to the Ras superfamily that is involved in the formation and stabilization of E-cadherin-based cell-cell adhesion in epithelial cells [38][39][40]. Thus, Rap1 is a key mediator of integrin-mediated cell-ECM adhesion [41].…”

NADPH Oxidase 5 (NOX5) Overexpression Promotes Endothelial Dysfunction via Cell Apoptosis, Migration, and Metabolic Alterations in Human Brain Microvascular Endothelial Cells (hCMEC/D3)

“…Finally, endothelial cell cytoskeleton changes may increase cell permeability; for example, endothelial cells stimulated with curcumin are more permeable to monocyte migration [ 53 ]. Several groups have demonstrated how ERM complex and Rho GTPase signaling can mediate the endothelial infiltration of certain types of immune cells [ 54 , 55 , 56 ].…”

Using integrated GC-MS analysis, in vitro experiments, network pharmacology: exploring migao fatty oil active components/mechanisms against coronary heart disease

“…Rap1 is a member of the Ras family of small GTPases, and its activation improves vascular barrier function (Yamamoto et al, 2021). Rap1 mainly promotes nitric oxide release during laminar flow and mostly suppresses pro-inflammatory signals in the absence of laminar flow, hence guarding against atherosclerosis (Singh et al, 2021).…”