Caveolae: A Role in Endothelial Inflammation and Mechanotransduction?

Figures

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  Figure 1. The leukocyte adhesion cascade. The leukocyte adhesion cascade describes the process involving complex leukocyte to endothelium interactions. It involves the activation of the endothelium, which upregulates inflammatory signaling mechanisms through the release of inflammatory cytokines and chemokines. Circulating leukocytes are then recruited to the activated endothelium, where they firmly adhere via various classes of adhesion molecules. Once the leukocytes have reached an arrest phase, they crawl until they reach complete arrest and are able to transmigrate through the vessel wall and differentiate into macrophages (IL-4, Interleukin-4; IL-13, Interleukin-13; TNF-α, Tumor necrosis factor-alpha; MCP-1, Monocyte chemoattractant protein-1; ICAM-1, Intercellular cell adhesion molecule-1; VCAM-1, Vascular cell adhesion molecule-1; PECAM-1, Platelet endothelial cell adhesion molecule-1).

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  Figure 2. Endothelial mechanoreceptors. Ion channels: Various types of ion channels have been implicated in sensing shear stress. GPCR, G-protein-coupled receptors are demonstrated to be activated by shear stress; Caveola, Caveolae, membrane microdomains, are demonstrated to be involved in shear stress mechanotransduction; Adhesion proteins, Adhesion molecules expressed at the surface of the cells are exposed to shear stress and respond accordingly; Primary cilia, Protruding from the apical cell membrane, primary cilia sense, and signal the exterior shear stress; Glycocalyx, A transmembrane macromolecule, when exposed to shear stress undergoes a conformation change, which triggers signal transduction; TKR, Tyrosine kinase receptor is proposed to form a complex with integrin molecules to act as a mechanoreceptor.

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  Figure 3. Signaling proteins enriched in endothelial caveolae. Cav-1, Caveolin-1; Cav-2, Caveolin 2; TRPC, transient receptor potential channel; GPCR, G-protein-coupled receptor; Gq, heterotrimeric G protein; TRPV4, TRP cation channel subfamily V number 4; RTK, receptor tyrosine kinase; TGFβRI/II, Transforming growth factor beta type I and II receptors.

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  Figure 4. Caveolae-mediated mechanisms in inflammation. In the event of endothelial activation via inflammatory stimuli including shear stress, pressure or stretch, caveolae are proposed to play a mediatory role in downstream signaling pathways. Caveolae exert their effects through the inhibition of signaling cascades involved in the onset of inflammation through caveolin-1 directly interacting and binding to a number of signaling proteins including eNOS, TLR-4, and ERK. However, it is proposed that in disease states where there is a homeostatic imbalance in ROS:NO and subsequent endothelial activation, caveolae may disassemble, and in turn uncouple from signaling proteins. This results in upregulated activity and phosphorylation of signaling proteins key in inflammation, and thus enhance pro-inflammation transcriptional activity (ROS, reactive oxygen species; NO, nitric oxide; eNOS, endothelial nitric oxide synthase; ERK, extracellular signal-regulated kinases; TLR4, toll-like receptor 4; NFκB, nuclear factor kappa B; JNK, c-Jun N-terminal kinase; PAK, p21-activated kinase; BFCOL1, binding factor of a type-I collagen promoter; ECM, extracellular matrix).