Endothelial cells (ECs) contain an abundance of the molecular machinery necessary to generate tension via an actomyosin motor—actin and myosin, the key components of the microfilamentous cytoskeleton, represent a major portion of the total endothelial cellular protein content (15-20%). G-actin is a globular monomer that assembles reversibly to form polymerized actin fibers (or F-actin) conferring strength on structural elements regulating cell shape, particularly when accompanied by phosphorylated myosin. F-actin filaments within peripherally distributed cortical bands are essential for maintenance of endothelial integrity and basal barrier function. The actin microfilament cytoskeleton is a dynamic structure that undergoes rearrangement under the control of various actin binding, capping, nucleating, and severing proteins and is focally linked to multiple membrane adhesive proteins such as cadherin molecules, glycocalyx components, functional intercellular proteins of the zona occludens and zona adherens, and focal adhesion complex proteins. More than 80 actin-binding proteins have been identified and are critical participants in cytoskeletal rearrangement and tensile force generation, and serve to provide a high level of fine tuning of cell shape, adhesion, and orchestrated cell migration as well as regulation of endothelial junctional stability . Edemagenic agents, such as thrombin, initiate cytoskeletal rearrangement characterized by the loss of peripheral actin filaments with a concomitant increase in organized F-actin cables that span the cell as "stress fibers" (Figure 2). One actin binding protein, cofilin for example, exerts actin-depolymerizing activity critical to cortical actin rearrangement that is inhibited by Rho GTPase pathway activation during stress fiber formation . In addition, reduction in either expression or activity of the abundant actin-severing protein gelsolin significantly decreases stress fiber-dependent contraction in cultured cells. Another actin-binding protein involved in cellular contraction is the 27-kDa heat shock protein, hsp27, whose actin binding properties are altered by phosphoryla-tion through a p38 MAP kinase-driven pathway. Reduction of hsp27-induced inhibition of actin polymerization alone can produce stress fiber formation.
Manjno and Palade first observed ultrastructurally that lung EC exhibit a rounded morphology producing paracel-lular gaps during inflammatory edema , a finding similarly observed after thrombin or histamine challenge. This dramatic cell shape change was an early implication of direct involvement of endothelial structural components, particularly the dynamic actin-containing microfilament EC cytoskeleton. Focally distributed changes in tension/relaxation can be accomplished by regulation of the level of myosin light chain (MLC) phosphorylation and actin stress fiber formation. Formation of cytoplasmic stress fibers, critical to cellular contraction and increased intracellular tension, occurs via the coordinate activation of the small GTPase Rho and Ca2+/CaM-dependent myosin light chain kinase, which together increase the level of phosphorylated myosin light chains in a spatially distinct manner. The
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.