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.

15α-methoxypuupehenol Induces Antitumor Effects In Vitro and In Vivo against Human Glioblastoma and Breast Cancer Models

“…Although the array contained over 1300 proteins, the notable phospho-proteins that were altered dramatically in response to 15α-MP are shown in Supplementary Figure 2. These include targets whose functions impact cellular structurally-directed processes, such as pY731VE-cadherin, a glycoprotein of the cadherin superfamily involved in endothelial cell-cell adhesion (26), pY125WAVE1 (Wiskott-Aldrich syndrome protein), WASP family member involved in regulating the actin cytoskeletal organization (27), pS339CXCR4 a member of the chemokine receptors that regulates morphogenesis, angiogenesis and immune responses (28), and pS10merlin levels, which all increased in response to the treatment with 15α-MP, compared to control (Supplementary Figure 2). Other targets include pY478ezrin, pS147cyclinB1, and pY1507Alk levels, which decreased (Supplementary Figure 2).…”

“…Studies using the GBM cell model also reveal the modulation of other putative targets, including VE-cadherin (26), WAVE1 (27), pS339CXCR4 (28), merlin, ezrin, CyclinB1, Erk1/2, and Alk, which would constitute part of the mechanism leading to the antitumor responses to 15α-MP. Functionally, CyclinB1 is a known regulator of the cell cycle (40), Alk promotes growth and anti-apoptotic pathways (41), while ezrin, radixin, moesin (ERM), and merlin comprise the ERM family of proteins, which link membrane proteins to the actin cytoskeleton (34).…”

The role of apical cell–cell junctions and associated cytoskeleton in mechanotransduction

“…Mechanosensing at endothelial cell-cell junctions occurs through more complex mechanisms, when compared with epithelial cell models (reviewed in (Huveneers and de Rooij, 2013;Conway and Schwartz, 2015;Dorland and Huveneers, 2016)). Although endothelial cells can establish a more or less tight barrier through TJ, TJ are not clearly distinguishable from AJ by electron microscopy in endothelial cells.…”

Endothelial Nitric Oxide Synthase and Neurodevelopmental Disorders

“…Scientiic investigations of endothelial remodeling have conirmed its relevance to vascular barrier function, inlammation, and vascular disease [9].…”