Eceptor-2 (VEGFR2) and PI3 kinase (389). This and also other studies discovered PECAM-1 as a mechanosensor situated inside endothelial cell-cell adhesions. Interestingly, in vitro application of pulling forces directly on endothelial cell surface expressed PECAM-1 working with magnetic beads led to Erk activation, which was also observed in flow-exposed EC monolayers. These findings suggest that PECAM-1 may possibly sense mechanical forces generated by both flow-induced shear tension and mechanical stretch (116). Conway et al. not too long ago showed that as well as interacting with VEGFRs, VE-cadherin can regulate its binding to polarity protein LGN (also referred to as G-protein-signaling modulator) to confer endothelial responses to shear tension (78).Author Manuscript Author Manuscript Author Manuscript Author ManuscriptCompr Physiol. Author manuscript; Akt1 Inhibitor Synonyms accessible in PMC 2020 March 15.Fang et al.PageGap junctions and their interactions with adherens junctions in mechanosensingAuthor Manuscript Author Manuscript Author Manuscript Author ManuscriptGrowing as monolayers in vivo, endothelial cells might sense and transmit mechanical forceinduced signals by propagating Ca2 + signaling via gap junctions. Molecular analysis identified Connexin-32 as gap junction proteins especially involved in mechanically induced propagation of Ca2 + waves in airway epithelial cell monolayers (49). The connexins mediating stretch-induced signal propagation in endothelium remains to become identified. Force application to adherens junction protein N-cadherin in reside cells brought on activation of stretch-activated calcium-permeable channels and influx of extracellular Ca2 +. Force application to junctional N-cadherin also causes an increase of actin cytoskeleton at intercellular contacts suggesting that cadherins may well play a role as intercellular mechanotransducers (196). Large numbers of cells ( 105) form synchronous cell-cell contacts which can transduce Ca2 + signals across the monolayer and require fast formation of adherens junction-like structures and their colocalization with gap junctional complexes. Thus, dynamic relationships amongst newly formed adherens junction-like structures and gap junctional complexes [described in fibroblasts (195)] appear to be important for establishing cell-cell communication and could also play an essential role in mechanosensing and mechanotransduction by endothelial cells. Cytoskeleton The cytoskeletal network plays an crucial function in endothelial mechanosensing and mechanotransduction. A “tensegrity” model (165) considers the cytoskeletal components (microfilaments, RGS4 Species microtubule, and intermediate filaments) as an interconnected network, where the microfilaments and intermediate filaments bear tension plus the microtubules bear compression. This model explains the capacity from the cell to execute complicated processes which include spreading, migration, and how forces applied locally on the cell lead to responses throughout the entire cell. Intracellular strain transmission via subcellular structural components affects activation of localized mechanosensing sites including focal adhesions in adherent cells. A study by Deguchi et al. (88) investigated force balance within the basal actomyosin strain fibers and focal adhesion complexes in smooth muscle and endothelial cells. Removal of mechanical restrictions for tension fibers (for instance dislodging of cell ends in the substrate) resulted within a lower in the length from the remaining actin fibers. Moreover, a release with the p.
