Cell-cell junctional mechanotransduction in endothelial remodeling

Abstract

The vasculature is one of the most dynamic tissues that encounter numerous mechanical cues derived from pulsatile blood flow, blood pressure, activity of smooth muscle cells in the vessel wall, and transmigration of immune cells. The inner layer of blood and lymphatic vessels is covered by the endothelium, a monolayer of cells which separates blood from tissue, an important function that it fulfills even under the dynamic circumstances of the vascular microenvironment. In addition, remodeling of the endothelial barrier during angiogenesis and trafficking of immune cells is achieved by specific modulation of cell-cell adhesion structures between the endothelial cells. In recent years, there have been many new discoveries in the field of cellular mechanotransduction which controls the formation and destabilization of the vascular barrier. Force-induced adaptation at endothelial cell-cell adhesion structures is a crucial node in these processes that challenge the vascular barrier. One of the key examples of a force-induced molecular event is the recruitment of vinculin to the VE-cadherin complex upon pulling forces at cell-cell junctions. Here, we highlight recent advances in the current understanding of mechanotransduction responses at, and derived from, endothelial cell-cell junctions. We further discuss their importance for vascular barrier function and remodeling in development, inflammation, and vascular disease.

Keywords: Adherens junction; Cardiovascular disease; Catenin; Cytoskeleton; Endothelial integrity; Mechanosensing; PECAM-1; Permeability; Vascular stiffness.

Fig. 1

Mechano-transduction events during remodeling of endothelial adherens junctions. A model depicts remodeling phases of the VE-cadherin complex in response to pulling forces. In stable monolayers, cell–cell adhesions are organized as continuous linear adherens junctions (LAJs). This conformation is promoted by Rac-driven cell protrusions which lower tension on the VE-cadherin complex and allow the formation of cortical F-actin bundles. Together, these events support cell–cell adhesions and enhance barrier function. Cytoskeletal dynamic is responsible for a kinetic system of actin-bound and -unbound states of the VE-cadherin complex, in which pulling forces from the actomyosin cytoskeleton stabilize a direct interaction of F-actin with unfolded junctional α-catenin. Permeability agonists that stimulate Rho-mediated actomyosin contractility induce the formation of tensile radial F-actin bundles, which pull on the VE-cadherin complex. High pulling-derived tension destabilizes cell–cell adhesions, which adopt a discontinuous focal adherens junction (FAJ) organization, and induce endothelial permeability. Tension-induced binding of vinculin to α-catenin marks the formation of FAJs, and is responsible to protect these junctions from opening too far. Simultaneously, several actin remodeling proteins, including zyxin, VASP, and TES, are recruited to FAJs upon cytoskeletal-derived pulling

Fig. 2

Mechano-transduction events during endothelial sensing of laminar flow. Shear forces derived from the bloodstream promote endothelial signaling. This occurs via a mechanotransduction complex consisting of the junctional adhesion proteins PECAM-1 and VE-cadherin in conjunction with activation of VEGF receptors. Subsequently, activation of signaling pathways controlled by Src, Rho, and PI3K mediates cytoskeletal remodeling and activation of basal integrins which support alignment of the endothelial cells in the direction of flow