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Shear Stress, Mechanosensors, and Atherosclerosis
Published in Juhyun Lee, Sharon Gerecht, Hanjoong Jo, Tzung Hsiai, Modern Mechanobiology, 2021
Similar to PECAM1 tyrosine phosphorylation, flow also rapidly induces VEGFR2 phosphorylation [37]. In 2008, Tzima et al. discovered a mechanosensitive complex composed of PECAM1/ VEGFR2/VE-cadherin that is responsible for mechanosensing and mechanotransduction [38]. Classically, PECAM-1 induced Src kinase–dependent phosphorylation and transactivation of VEGFRs. VE-cadherin could possibly function as an adaptor [37]. Recent studies have shown that flow shear stress induced VE-cadherin phosphorylation at Tyr 658 [37]. Recently studies have also revealed that VEGFR3 also forms a complex, thus adding a new component in the mechanosensing complex [39, 40]. In terms of the role of PECAM1 in atherosclerosis, in 2008, two independent groups independently showed in two different mouse models of atherosclerosis (apolipoprotein E knockout [ApoE–/–] mice and low-density-lipoprotein receptor–deficient [LDLr–/–] mice), that PECAM1 affects atherosclerosis in a site-dependent manner, suggesting that PECAM1 could perform dual functions depending on the patterns of blood flow [41, 42]. Specifically, PECAM-1 deletion inhibits NF-icB-dependent VCAM-15 expression when exposed to disturbed flow [41].
Centralized Endothelial Mechanobiology, Endothelial Dysfunction, and Atherosclerosis
Published in Jiro Nagatomi, Eno Essien Ebong, Mechanobiology Handbook, 2018
Ian Chandler Harding, Eno Essien Ebong
Of these proteins, the interendothelial junction proteins VE-cadherin and PECAM-1 have demonstrated significant potential as endothelial mechanotransducers. For example, these proteins have been implicated in shear stress regulation of cell adhesion receptor expression, cell permeability, and eNOS expression, among others (Table 7.1) [75,89,90]. However, removal of cytoskeletal stress fibers has been shown to significantly decrease transmission of shear force to the cell-to-cell junctions [146]. This highlights the importance of the cell-to-cell junctions in decentralized mechanotransduction and not centralized mechanotransduction. When the cytoskeleton is intact, transmission of shear stress through the cell can lead to substantial force application at the cell-to-cell junctions [146]. This is highlighted using computational modeling, where Dabagh et al. found that the application of 10 dynes/cm2 of shear stress generated somewhere between 0.4 and 4 pN of force on cell-to-cell junctional proteins [146]. Based on previous in vitro experiments, this force lies within a range sufficient to induce conformational changes in PECAM-1 [156,157]. This can lead to the activation of various signaling pathways that lead to important downstream responses.
Elevated shear rate-induced by exercise increases eNOS ser1177 but not PECAM-1 Tyr713 phosphorylation in human conduit artery endothelial cells
Published in European Journal of Sport Science, 2023
Andrea Tryfonos, Debar Rasoul, Daniel Sadler, James Shelley, Joseph Mills, Daniel J. Green, Ellen A. Dawson, Matthew Cocks
At the time of analysis, cells were rehydrated in DPBS for 5 min. After blocking nonspecific binding sites with 5% donkey serum (1 h) (Sigma Aldrich, USA), cells were incubated for 1 h at room temperature with primary antibodies against eNOS (610297, BD, USA), eNOS phosphorylated at Ser1177 (peNOS Ser1177) (07-428-I, Merck), PECAM-1 (abc24590, Abcam, UK) and PECAM-1 phosphorylated at Tyr713 (BS4666, Bio World, USA). Cells were also stained for vascular-endothelial (VE)-cadherin (NB600-1409, Novus, UK) for positive identification of the endothelial phenotype. Cells were then incubated with appropriate secondary antibodies, in combination with DAPI (4-6-diamidino-2-phenylindole hydrochloride) for assessment of nuclear integrity. Finally, coverslips were mounted in a glycerol and mowiol 4–88 solution in 0.2 m Tris buffer (pH 8.5) with addition of 0.1% DABCO anti-fade medium.
Magnetic stimulation of the angiogenic potential of mesenchymal stromal cells in vascular tissue engineering
Published in Science and Technology of Advanced Materials, 2021
Ana C. Manjua, Joaquim M. S. Cabral, Carla A. M. Portugal, Frederico Castelo Ferreira
VEGF-A, a potent angiogenic factor and often released as a cell-survival signal, is one of the most important paracrine factors involved in the regulation of the interactions between MSCs and endothelial cells leading to formation of microvessel-like structures [4,8,12]. This molecule has been exhaustively studied as a target molecule to stimulate or inhibit angiogenic phenomena [4,8,12,13]. Some papers have reported how the induced mobilization of VEGF from bone marrow-derived endothelial progenitor cells is able to potentiate cells differentiation in vitro as well as trigger neovascularization in vivo [4,14]. Other studies demonstrated that MSCs are capable of inhibiting endothelial proliferation and angiogenesis through cell-cell contact and modulation of the VE-cadherin/ß-Catenin signaling pathways [15]. Still a powerful challenge in this emerging field involves the development of a controlled system to stimulate the secretome of MSCs into releasing cell-survival signals to promote the formation of microvessel-like structures.
Methanolic extract of Teucrium persicum up-regulates and induces the membrane restoration of E-cadherin protein in PC-3 cells
Published in International Journal of Environmental Health Research, 2023
Majid Tafrihi, Anahita Naeimi, Fatemeh Eizadifard
E-cadherin (also called uvomorulin, L-CAM, cell CAM 120/80, CDH1, CD324, or Arc-1) is a 120 kDa transmembrane glycoprotein, that is encoded by the CDH1 gene (16q22) (Van Roy and Berx 2008). This protein belongs to the classical cadherin subfamily of the cadherin superfamily. Type I and type II classical cadherins are E-cadherin (CDH1), N-cadherin (CDH2), P-cadherin (CDH3), R-cadherin (CDH4), VE-cadherin (CDH5), K-cadherin (CDH6), and M-cadherin (CDH15) that interact with catenin proteins through their cytoplasmic domain (Saito et al. 2012; Bruner and Derksen 2018).