Microfilaments and microtubules maintain endothelial integrity

Abstract

The endothelium is a highly metabolic monolayer of cells regulating numerous physiological and pathological functions that maintain the permeability and thromboresistant functions of the endothelium. The structure and function of the endothelial cytoskeleton prevents vascular disease by regulating the structure of the endothelium to act as a resting molecular barrier to atherogenic proteins and by becoming an activated layer of migrating cells to repair denuding injuries. The purpose of this review is to examine the structure of the endothelial cytoskeleton and its roles in cell-cell and cell-substratum adhesion, cell signaling, and regulation of wound repair. Studies focused on the cellular and molecular biology of the structure and function of the endothelial cytoskeleton and in wound repair are reviewed. The cytoskeleton is a key regulator in maintaining endothelial integrity and in restoring integrity following injurious denudation, such as those that occur in the pathogenesis of atherosclerosis. Actin microfilaments and their associated adherens junctions and focal adhesions are important regulators of cell signaling, cell locomotion, cell adhesion, and wound repair mechanisms. Various proteins have been implicated in controlling cytoskeletal-based endothelial function and repair such as tyrosine kinases/phosphatases and the Rho family of proteins. The normal function of the endothelium is highly dependent on the endothelial cytoskeleton. Disruption and dysfunction of the cytoskeleton may result in impairment of endothelial function, subsequently tipping the balance towards vascular disease. Thus, an understanding of the cellular and molecular biology of the endothelial cytoskeleton is essential in our understanding of the pathogenesis of vascular disease, especially atherosclerosis.

LIM Kinase 1 Coordinates Microtubule Stability and Actin Polymerization in Human Endothelial Cells

“…Recent studies suggest direct involvement of MTs in the regulation of endothelial integrity and wound repair, as depolymerization by the microtubule inhibitors nocodazole and vinblastine results in rearrangement of the actin cytoskeleton, increased stress fiber formation, cell contraction, and permeability (6,28). Here we showed that LIMK1 could induce MTs destabilization (Fig.…”

Multiparametric MRI biomarkers for measuring vascular disrupting effect on cancer

“…Dysfunction in cellular shape can cause subsequent vascular hyperpermeability [22] . The cytoskeleton consists of three distinct components: microtubules, actin microfilaments and intermediate filaments [23] , and the former two are associated via linking proteins, which, in turn, interact with these two cytoskeletal components for signaling [24] . As the scaffolding of the cell, the cytoskeleton plays a vital role in cell motility, division, shape maintenance, and signal transduction [24] .…”

“…CA4P selectively binds to microtubules and depolymerizes tubulin, which results in the activation of RhoGTPase and its associated Rho kinase [34][35][36] (Figure 1). Activation of the Rho/Rho-kinase pathway may cause downstream morphological and/or functional changes in ECs, which can lead to dysmorphism and hyperpermeability: (1) assembly of actin stress fibers and fortified contractility of ECs [24] ; (2) disruption of the VE-cadherin/β-catenin complex to induce the loss of intercellular adhesion and the appearance of paracellular gaps [22] ; (3) blebbing of ECs with regulation of stress-activated protein kinase p38 (SAPK-2/p38) to bring about increased monolayer permeability and resistance to blood flow [36,37] ; and (4) vasoconstriction to give rise to increased geometric resistance to blood flow [38] . In addition, the direct binding of CA4P to tubulin compromises the integrity of cytoskeleton, and morphological changes of endothelial monolayer architecture further deteriorates [7,39] (Figure 1).…”

The role of cytoskeleton in the regulation of vascular endothelial barrier function

“…Many signal proteins translocation and activity rely on microtubules; in particular, Rho family GTPases and their regulatory proteins were shown to be tightly associated with polymerized tubulin [Lee, Gotlieb, 2003]. It is not surprising then that the state of actin cytoskeleton, tightly regulated by Rho, depends on microtubule polymerization/depolymerization status.…”

“…The attachment of cortical ring to membrane and its dynamic rearrangement is modulated by the array of actin and/or membranebinding proteins. The equilibrium between the centripetal and centrifugal forces is a subject to the regulation by several signaling pathways [Lee, Gotlieb, 2003; *Address reprints requests to: Alexander D. Verin, Vascular Biology Center, CB-3210A, Medical College of Georgia, Augusta, Georgia 30912-2500. Office: 706-721-1531;Fax: 706-721-9799; Email: averin@mcg.edu.…”