ReviewMolecular basis of the effects of shear stress on vascular endothelial cells
Introduction
Blood vessels are constantly exposed to hemodynamic forces in the form of cyclic stretch and shear stress due to the pulsatile nature of blood pressure and flow. Although vascular endothelial cells (ECs) and vascular smooth muscle cells (SMCs) are exposed to both types of mechanical forces, the shear stress resulting from blood flow is borne primarily by ECs, whereas SMCs are primarily subjected to cyclic stretch resulting from pulsatile pressure. This review focuses on the effects of shear stress on ECs. The effects of mechanical stretch on SMCs will be covered in a separated review.
The EC monolayer not only provides a selective barrier for macromolecular permeability between the blood and the vessel wall but also serves a number of important homeostatic functions. Thus, ECs influence vascular remodeling via the production of growth-promoting and growth-inhibiting substances; modulate hemostasis and thrombosis through the secretions of pro-coagulant, anti-coagulant, and fibrinolytic agents; mediate inflammatory responses through the expression of chemotactic and adhesion molecules on their membrane surfaces; and regulate vascular SMC contraction through the release of vasodilators and vasoconstrictors. Impairment of these functions may lead to pro-atherogenic and/or pro-thrombotic states and hence atherosclerosis and/or thrombosis (Badimon et al., 1992; Blann and Lip, 1998; Quyyumi, 1998). Blood flow is disturbed and unsteady at the atherosclerosis-prone regions of the arterial tree (branch points and curved areas) in contrast to the relatively simple laminar flow in the straight parts of the aorta. Experiments using cultured ECs in flow channels in vitro allow the control of chemical and mechanical factors, thus facilitating the investigation of cellular responses to different types of shear flow. In this review, the term “shear stress” is used to designate that resulting from simple laminar flow (usually with a shear stress of 10–20 dyn/cm2, or 1–2 Pa), which was used in most investigations, unless otherwise noted (e.g., disturbed flow studied in a step flow channel).
Section snippets
Mechano-sensors for shear stress
ECs act as a sensing interface to transduce hydrodynamic forces. Studies by others and our group suggest that integrins, vascular endothelial growth factor (VEGF) receptor-2 (Flk-1), ion channels, G-protein-coupled receptors (GPCRs) and trimeric G proteins, and adhesion molecules such as platelet endothelial cell adhesion molecule-1 (PECAM-1) are involved in the sensing of shear stress by ECs. The findings reviewed below indicate that multiple molecular elements are involved in sensing the
Shear stress modulation of EC signaling pathways
Studies on intracellular signaling events in ECs have shown that shear stress activates multiple signaling molecules, including protein kinase C (PKC), FAK, c-Src, Rho family GTPases, PI3K, and MAPKs. Thus, shear stress can activate multiple mechano-sensing molecules (Section 2.1) and lead to the initiation and propagation of signals through a network of pathways.
PKCs, which are a family of multifunctional enzymes activated by diacylglycerol, play an important role in signal transduction and
Effects of shear stress on EC gene expression
Flow channel studies with Northern blotting or RT–PCR have shown that shear stress regulates EC gene expression (reviewed by Davies, 1995; Chien et al., 1998). For example, shear stress increases the transcripts of PDGF-A and -B (Hsieh et al., 1991; Resnick et al., 1993), basic fibroblast growth factor (Malek et al., 1993a), heparin-binding epidermal growth factor-like growth factor (HBEGF) (Morita et al., 1993), and transforming growth factor-β (TGF-β) (Ohno et al., 1995). Shear stress
Effects of shear stress on EC proliferation
There is considerable evidence that the growth status of ECs can be regulated by the type of shear stress to which they are exposed. Earlier studies have shown that laminar shear stress causes a dose-related reduction of the rate of EC proliferation (Levesque et al., 1990). It has also been shown that ECs subjected to a long duration of laminar flow at sufficiently high shear stresses have a lower rate of DNA synthesis than ECs under static condition (Mitsumata et al., 1997). Recent experiments
Physical aspects of the effects of mechanical shearing on ECs
The biologic responses of cells to shear stress could involve many biomechanical or biophysical aspects. There is the possibility that the electrokinetic fields created by fluid flow over the EC surface may induce the changes observed in ECs. Hung et al. (1996) showed that the convective current density does not affect [Ca2+]i in bone cells exposed to shear stress, but there have been no similar studies with ECs. Recent theoretical models of the response of cytosolic free calcium in ECs to
Responses of ECs to different flow patterns
The interplay of the cardiac cycle and the vessel geometry results in the pulsatile nature of blood flow and the asymmetric shape of the velocity profile (Nerem et al., 1974, Nerem et al., 1976), thus leading to temporal and spatial variations of the wall shear stress. In the straight part of the vessel, the blood flow is relatively undisturbed, with a mean shear stress ranging from 10 to 70 dyn/cm2 (Nerem et al., 1998). However, the blood flow patterns in bends and bifurcations are disturbed
In vivo significance of the actions of shear stress on ECs
Atherosclerotic lesions in humans (Packham et al., 1967; Wissler, 1995) and experimental animals (Schwenke and Carew, 1988, Schwenke and Carew, 1989a) occur preferentially at branch points and curved regions of the arterial tree, i.e., areas where the shear stress is low with a high spatial gradient and blood flow is disturbed and unsteady (Glagov et al., 1988; Ku et al., 1985). Systematic mapping of atherosclerotic lesions in the human arterial tree has shown that this distribution pattern is
Summary and conclusions
Shear stress regulates EC functions through multiple sensing mechanisms, leading to the activation of signaling networks, which in turn regulate gene expressions and functional responses (Fig. 12). ECs respond differentially to different modes of shear forces, e.g., laminar, disturbed, or oscillatory flows. As summarized in this review, in vitro studies on cultured ECs in flow channels have allowed the analysis of the molecular mechanisms by which cells convert the mechanical stimuli into
Acknowledgements
This work was supported in part by research grants HL19454, HL43026, and HL64382 and training grant HL07089 from the National Heart, Lung, and Blood Institute and a Development award from Whitaker Foundation. J.H.H. is a recipient of an NHLBI NRSA HL071390. The authors would like to acknowledge Dr. Pin-Pin Hsu for the work on EC proliferation in a step flow channel.
References (225)
- et al.
Differential display and cloning of shear stress-responsive messenger RNAs in human endothelial cells
Biochemical and Biophysical Research Communications
(1996) A model for shear stress-induced deformation of a flow sensor on the surface of vascular endothelial cells
Journal of Theoretical Biology
(2001)- et al.
Microarraysthe use of oligonucleotides and cDNA for the analysis of gene expression
Drug Discovery Today
(2003) - et al.
The retinoblastoma protein pathway and the restriction point
Current Opinion in Cell Biology
(1996) - et al.
Aortic endothelial permeability to albuminfocal and regional patterns of uptake and transmural distribution of 131I-albumin in the young pig
Experimental and Molecular Pathology
(1974) - et al.
Fluid shear stress activation of IkappaB kinase is integrin-dependent
Journal of Biological Chemistry
(1998) - et al.
Shear stress stimulates phosphorylation of endothelial nitric-oxide synthase at Ser1179 by Akt-independent mechanismsrole of protein kinase A
Journal of Biological Chemistry
(2002) - et al.
Integrin-mediated cell adhesion activates mitogen-activated protein kinases
Journal of Biological Chemistry
(1994) - et al.
Ultrastructural studies on macromolecular permeability in relation to endothelial cell turnover
Atherosclerosis
(1995) - et al.
Mechanotransduction in response to shear stress
Roles of receptor tyrosine kinases, integrins, and Shc. Journal of Biological Chemistry
(1999)