© 2004 by European Society of Cardiology
Copyright © 2004, European Society of Cardiology
Mechanical influence of cyclic stretch on vascular endothelial cells
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Received 5 June 2004; accepted 21 June 2004
See article by Von Offenberg Sweeney et al. [3] (pages 625–634) in this issue.
Most of the biological phenomena acting on arterial vessels are non-linear. The biological response of cells to mechanical stimuli differs substantially depending on whether they are exposed to static or pulsatile stress [1]. Since the first work by Glagov and his group [2], the role of cyclic hemodynamic forces has been emphasized. In the present issue, Von Offenberg Sweeney et al. [3] have studied the role of cyclic strain on the endothelial matrix metalloproteinase-2 expression and activity. They have also shown the importance of metalloproteinases within the frame of vascular remodeling and its consequences in clinical situations.
Endothelial cells (ECs) are mainly exposed to blood shear stress in the direction of blood flow but are also submitted to cyclical circumferential stretch that is tangential to the direction of blood flow. Pulsatile pressure is a major determinant of vessel stretch. Although the effects of cyclical mechanical stretch on vascular smooth muscle cells (SMCs) have been widely studied [4], its effects on ECs have received less attention and are the main focus of the work of Von Offenberg Sweeney et al. [3].
The authors used a Flexercell Stress Unit (Flexercell, USA) that mimics the effects of cyclic strain on cultured SMCs or ECs. This method permits the measurement of cellular elongation in response to deformation of the elastomere base of the culture plates. Other studies have used long-term organ cultures for arterial segments, which permits the application of physiological or supra-physiological levels of pulsatile intraluminal pressure. This method has the advantage of allowing one to study separately the effects of pressure and those of flow rates and to maintain intact cell–matrix interactions.
Both mechanical and growth factors have been implicated in the growth response of SMCs [5]. Angiotensin II (Ang II), a potent mitogen in these cells, has been shown to stimulate an increase in platelet-derived growth factor (PDGF) expression. Cyclic mechanical strain activates the mitogen-activated protein kinase (MAPK) pathway, promoting cell proliferation. Integrins, which act as mechanoreceptors, may activate MAPK via two major pathways, one involving focal adhesion kinase (FAK) and the other, the protein Shc. In contrast to cultured cells, exposure of intact aortas in culture to intraluminal pressure produced an increase in protein synthesis without a growth response. The local role of endogenous Ang II has been used to explain the increase in fibronectin synthesis by high blood pressure in aortic organ culture [1]. The mechanisms of the Ang II response involved a rapid increase in the expression of transcription factors such as egr-1, c-fos, and c-jun in SMCs prior to SMC hypertrophy. The difference between the cultured cell model and the organ culture of aorta is likely due the presence of endothelium, extracellular matrix (ECM) components, and the maintenance of a differentiated phenotype of SMCs within the intact vessel that may be involved in a negative control of SMC growth. Integrin–ECM interactions in a focal adhesion complex and the specificity of these attachments play certainly a crucial role in the SMC response to mechanical strain. Changes in metalloproteinase activity do not seem to contribute to the increase in matrix proteins seen in SMCs exposed to mechanical strain. However, a recent study in mice showed that activation of matrix MMP-9 in the carotid artery exposed to static high blood pressure in vitro contributes to increased carotid distensibility [6].
The effects of cyclic mechanical stretch on ECs have been less thoroughly investigated. By themselves and by virtue of their location at the interface between blood and the media, ECs may modulate the effects of mechanical forces on SMCs. Wang et al. [7] have shown that cyclic mechanical stretch induces expression and activation of metalloproteinases 14 and 2 in cultured human endothelial cells. Mechanisms involved increased production of tumor necrosis factor-
(TNF-) through the JNK pathways. Activation of various proteases such as plasmin and elastase by cyclic stretch may also induce endothelial cell detachment and apoptosis (called anoïkis) [8]. It has been reported that an increase in the expression of metalloproteinases may modulate functional adaptation and remodeling of resistance arteries in hypertension. In intact vessels, Sipkema et al. [9] have shown that cyclic axial stretch in the absence of shear stress produces realignment of endothelial actin stress fibers toward the circumferential direction within a few hours. The functional consequence of the modification of this cytoskeletal organization is the loss of endothelium-dependant vasodilation while there is no difference in SMC function. The effects of axial stretch on ECs may become important in arterial regions of low shear stress considered as areas that are able to develop atherosclerotic plaques. Integrins and integrin/cytoskeletal interactions play a major role in endothelial mechanotransduction both to shear stress and blood pressure [10]. Stretch-activated ion channels and stretch-mediated changes in membrane potential also play a central role in endothelial cell mechanotransduction. Cyclic stretch and shear stress result in the activation of various signaling cascades inside the cell, including activation of Akt, tyrosine kinases like FAK and Src, MAP kinase, and small G proteins. However, it is still unknown whether circumferential stretch may activate an endothelial response and signaling that are distinct from the response to increased shear stress.
Using DNA microarray techniques, it has been demonstrated that cyclic strain in human cultured SMCs increases the expression of cyclooxygenase-1, tenascin-C, and plasminogen activator inhibitor-1, whereas matrix metalloproteinase-1 and thrombomodulin genes are downregulated [11]. These results have been interpreted as an adaptive response against excessive deformation. Strain also increased several genes for proteoglycan synthesis that play a major role in cell attachment to ECM components [12]. In pulmonary ECs, Birukov et al. [13] have shown a novel group of genes regulated by cyclic stretch, including the small GTPase rho, apoptosis mediator ZIP kinase, and proteinase-activated receptor-2, which can contribute to cyclic-stretch-mediated endothelial cell barrier disruption.
Effects of cyclic strain on endothelium function are of clinical importance. The necessity of drug treatment in hypertension is mainly based on the evaluation of cardiovascular (CV) risk. The risk is traditionally considered as linear and quantified from the relation between CV events and the level of systolic or diastolic blood pressure (BP). Systolic BP is, in fact, no more than a single and arbitrary point of the cyclic BP curve. CV risk would be better evaluated based on the totality of the BP curve or by using its surrogates: mean BP, the steady component of the BP curve, and pulse pressure (PP), its pulsatile component [14]. Many epidemiological studies [15] have shown that, mainly above 60 years of age, PP was the stronger predictor of CV risk, a finding which highlights the role of pulsatile stress of the arterial wall and may thus modify the classical aspects of anti-hypertensive therapy. Von Offenberg Sweeney et al. [3] note that not only the level of mechanical strain is important but also the number of cycles per time unit should be determined. In humans, heart rate is an independent predictor of CV risk, and the product of PP and heart rate is an even stronger predictor, particularly for coronary risk [16]. Experimentally, the changes in this product are associated with changes in the hysteresis of the arterial wall, leading to an increase in energy dissipation.
In animal and human studies, only the interactions between pulsatile signal and ECM may be investigated. It is very difficult to determine whether pulsatile pressure damages the arterial wall or whether the increased stiffness of the vessel is responsible for the increase in PP. Finally, the links between cyclic strain, pulse pressure, and collagen degradation through changes in metalloproteinases remain to be established.
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