Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell

Abstract

Chien S. Mechanotransduction and endothelial cell homeostasis: the wisdom of the cell. Am J Physiol Heart Circ Physiol 292: H1209 -H1224, 2007. First published November 10, 2006; doi:10.1152/ajpheart.01047.2006.-Vascular endothelial cells (ECs) play significant roles in regulating circulatory functions. Mechanical stimuli, including the stretch and shear stress resulting from circulatory pressure and flow, modulate EC functions by activating mechanosensors, signaling pathways, and gene and protein expressions. Mechanical forces with a clear direction (e.g., the pulsatile shear stress and the uniaxial circumferential stretch existing in the straight part of the arterial tree) cause only transient molecular signaling of pro-inflammatory and proliferative pathways, which become downregulated when such directed mechanical forces are sustained. In contrast, mechanical forces without a definitive direction (e.g., disturbed flow and relatively undirected stretch seen at branch points and other regions of complex geometry) cause sustained molecular signaling of pro-inflammatory and proliferative pathways. The EC responses to directed mechanical stimuli involve the remodeling of EC structure to minimize alterations in intracellular stress/strain and elicit adaptive changes in EC signaling in the face of sustained stimuli; these cellular events constitute a feedback control mechanism to maintain vascular homeostasis and are atheroprotective. Such a feedback mechanism does not operate effectively in regions of complex geometry, where the mechanical stimuli do not have clear directions, thus placing these areas at risk for atherogenesis. The mechanotransduction-induced EC adaptive processes in the straight part of the aorta represent a case of the "Wisdom of the Cell," as a part of the more general concept of the "Wisdom of the Body" promulgated by Cannon, to maintain cellular homeostasis in the face of external perturbations. feedback; gene expression; Rho GTPase; shear stress; signal transduction; strain ENDOTHELIAL CELLS (ECs), besides being a permeability barrier between the blood and vessel wall, perform many important functions, e.g., cell migration, remodeling, proliferation, apoptosis, and the production, secretion, and metabolism of biochemical substances, as well as the regulation of contractility of vascular smooth muscle cells (SMCs). In addition to their modulations by chemical ligands, ECs respond to mechanical factors, such as fluid shear stress and stretch, which can also be sensed by the EC to modify intracellular signaling, gene expression, and protein expression to result in functional regulations (Fig. 1).The mechanical stresses (forces per unit area, with a unit of dyn/cm 2 ) acting on the vessel wall include the normal and circumferential stresses that result from the action of pressure and the shear stress that acts parallel to the luminal surface of the vessel due to flow (Fig. 2). The circumference stress acts along the vessel wall perimeter to cause stretching. The shear stress acts parallel to the...

Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt Pathways

“…Consistent with the model that mechanical loading increases bone development, we also found that expression of ALP and OC was indeed increased after 48 hours of stretching. The transient downregulation of bone marker genes after 24 hours may be explained by the possibility that mechanical loading initially serves as a mitotic signal (54) that results in increased expression of proliferation-associated genes and decreased expression of bone differentiation markers. Sustained mechanical loading, however, resulted in growth arrest (55,56) and favored differentiated states, as indicated by the increase in OC and ALP expression after 48 hours of mechanical loading.…”

p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress‐induced angiogenesis

“…This hemodynamic stimulus activates numerous mechanoreceptors on the endothelium such as integrins, G protein-coupled receptors, cell adhesion molecules, ion channels and receptor tyrosine kinases (Chien, 2007). Shear stress also activates numerous signaling molecules such as Protein kinase C, Focal adhesion kinase, c-Src, Rho family GTPases, Phosphoinositide 3-kinases and Mitogen activated protein kinases (MAPKs) (Li et al, 2005).…”

“…Shear stress also activates numerous signaling molecules such as Protein kinase C, Focal adhesion kinase, c-Src, Rho family GTPases, Phosphoinositide 3-kinases and Mitogen activated protein kinases (MAPKs) (Li et al, 2005). Transcription factors such as Ets-1 (Milkiewicz et al, 2008), NF-κB, Krüppel-like factor 2 (Chien, 2007), c-Myc, Activator protein 1 and T-cell factor (Li et al, 2005) are known to be regulated by shear stress.…”

“…VEGFR2 is known to initiate multiple downstream signaling pathways including the activation of Ras/MEK/ERK, Src, PI3K/Akt, HSP90, focal adhesion kinase and p38 (Traub and Berk, 1998;Le Boeuf et al, 2004;Jin et al, 2005). Shear stress increases endothelial nitric oxide synthase (eNOS) phosphorylation and nitric oxide (NO) production via activation of Akt (Jin et al, 2003), and induces phosphorylation of ERK1/2 and p38 MAPKs (Chien, 2007;Milkiewicz et al, 2006). Sequestration of VEGF or inhibition of nitric oxide synthase (NOS) activity abolishes shear stress-mediated luminal projection formation and angiogenesis (Williams et al, 2006;Baum et al, 2004).…”

Anisotropic rheology and directional mechanotransduction in vascular endothelial cells

“…The structural reorganization of cytoskeleton leads to changes in subcellular microrheology that can play an important role in mechanosensing and signaling by redistributing the external forces among intracellular subdomains (6,7). Existing evidence suggests that changes in subcellular microrheology, including directionality and polarity, could provide a mechanism for cells to sense external forces and their direction, modulate intracellular signaling, and regulate gene expression and cell turnover (8).…”