Endothelial Function Mechanical Stress and Atherosclerosis

Daniel Hayoz Lucia Mazzolai

Department of Medicine, Vascular Medicine, CHUV, Lausanne, Switzerland


Atherosclerosis and its complications represent the leading cause of morbidity and mortality in the industrialized as well as in the developing countries. Classical cardiovascular risk factors have been identified over the past decades leading to recommendations for life style modifications and to the development of efficient and well-tolerated drug regimens aimed at reducing the occurrence of cardiovascular complications. The endo-thelium due to its position in the circulation is the first organ being exposed to circulating noxious elements and solutes as well as to the mechanical aggressions generated by heartbeats and pulsating blood flow. This review addresses the relevance of the combined effects of the mechanical stress and cardiovascular risk factors on the early phases of atherosclerosis.

Copyright © 2007 S. Karger AG, Basel

This chapter on endothelium involves four sections: normal endothelial function; effect of atherosclerosis; role of mechanical stress, and relation between arterial stiffness and endothelial function.

Normal Endothelial Function

The endothelium is a monolayer of endothelial cells lining the vascula-ture. It lies at the interface of the vessel wall and the circulating blood and constitutes a protective barrier between the two elements. Endothelial cells play a crucial role in maintaining vascular homeostasis. They function as sensors and integrators of hemodynamic and hormonal stimuli and they control the bidirectional transport of macromolecules and blood gases through the vascular wall [1], As a result, endothelial cells release a number of autocrine and paracrine factors that regulate vascular permeability, vasomotion, coagulation, cell adhesion, inflammation and mitogenesis [2], Disruption of the balanced release of these bioactive factors can be a critical factor in the pathogenesis of vascular diseases and more specifically of atherogenesis.

It is now well established that endothelial dysfunction is a very early event if not the earliest in the process of atherogenesis and therefore, testing endo-thelial function may serve as a biomarker of lesion formation [3]. For this reason it became manifest that evaluation of endothelial function integrity was of utmost importance in vascular biology both in clinical as well as in experimental conditions. Impairment in endothelial function has been related to all known atherogenic risk factors (dyslipidemia, hypertension, smoking, diabetes mellitus, aging, menopause...). Several studies have now recognized the prognostic value of endothelial dysfunction for atherothrombotic complications [4-8]. Although endothelial dysfunction may not homogeneously affect the vascular bed, strong evidence suggests that a close relationship exists between human peripheral artery and coronary vasomotor abnormalities leading to the concept of systemic endothelial dysfunction [9], As a consequence, endothelial function testing is no longer restricted to patients undergoing invasive cardiac catheterization. Originally, endothelial function was assessed during quantitative angiography by measuring the vasomotor response of epi-cardial arteries to increasing concentrations of muscarinic receptor agonists (acetylcholine, metacholine) [10]. Nowadays, it can be tested in the upper limb by measuring forearm blood flow using strain gauge plethysmography during intra-arterial infusion of muscarinic receptor agonists [11]. The brachial artery is the most frequent peripheral artery tested for this purpose. However, the test remains invasive and therefore limited to research centers. With the advent of high-resolution ultrasound technology, a totally non-invasive method was proposed to evaluate endothelial function [12, 13]. Reactive hyperemia following a localized ischemic stimulus, distal to the measuring site, generates an increased shear stress that induces nitric oxide (NO) release. This test, known as the endothelial-dependent flow-mediated dilation (FMD) of the conduit artery, is now widely used to test the integrity of endothelial function [14], As demonstrated years ago it is less sensitive than the muscarinic receptor challenge but much more practical and it can be applied to asymptomatic populations as well as to patients [10]. Indeed, subjects with cardiovascular risk factors and smooth coronary arteries show paradoxical vasoconstriction upon intracoronary acetylcholine infusion [10]. In patients with significant coronary artery disease, diagnosed at angiography, preserved although reduced FMD could still be observed despite significant vasoconstriction during ace-

Table 1. Current methods to assess in vivo endothelial function in human subjects


Vascular bed




Venous occlusion plethysmography

Forearm resistance vessels


Arterial cannulation Critical vasoconstriction

Highly accurate

Laser Doppler flowmetry (reactive hyperemia, iontophoresis)

Skin microvessels



High accuracy for acute pharmacological or physical challenges

Needs further validation

Flow-mediated dilation

Conduit arteries

Non-invasive (echo-Doppler) Invasive (flow-wire)


Critical vasoconstriction Arterial cannulation and dissection

Equipment-dependent (hardware, software)

PET scan

Resistance vessels

Non-invasive Very expensive


Highly accurate Needs further validation

Pulse wave analysis

Large and small arteries

Non-invasive Ease of use


Further characterization needed to establish association between arterial stiffness and endothelial function

tylcholine challenge. In the latter case, blood flow was increased by peripheral arteriolar dilation following papaverine infusion distally from the arterial segment under investigation.

Brachial artery FMD was shown to be predictive of clinical complications associated with atherosclerosis [9]. Although more easily available than the invasive techniques, brachial FMD assessment performed by high-resolution ultrasound remains quite a challenging test and requires appropriate qualification and training. In this respect, guidelines have been published to try to standardize the methods and protocols between centers in order to be able to compare results among investigators [14].

Recently, more practical and simpler devices have been designed to measure endothelial function (table 1). One such device uses a digital plethysmography technique based on an observation that was made earlier in hypercho-lesterolemic patients demonstrating reduced flow reserve and elevated resistance during hyperemia [15]. This system allows to assess endothelial function in a very simple way. Using this device, it has been demonstrated that digital reactive hyperemia response can identify patients with early coronary microvascular endothelial dysfunction [16]. Further studies will be needed to fully assess the potential of this simple and non-invasive endothelial function test.

Laser Doppler iontophoresis is another attractive technique requiring specific tools to assess skin microvascular endothelial function [17, 18]. The test is quite reproducible but several problems still need to be overcome such as variability in skin conductivity and current-induced vasodilation. As for the previously mentioned plethysmography method, further studies will be necessary to evaluate the prognostic value of skin microvascular dysfunction in detecting individuals at increased coronary heart disease (CHD) [19].

A number of circulating factors have been considered for their potential predictive value of endothelial function and atherothrombotic complications. Among them, highly sensitive CRP, which is closely related to systemic and vascular low-grade inflammation, has been identified as one of the most valuable factors. Elevated levels of circulating CRP have been shown to be closely associated with the increased 10-year risk of CHD, regardless of the presence or absence of known cardiac risk factors. A single CRP measurement provided information beyond conventional risk assessment, especially in intermediate-Framingham-risk men and high-Framingham-risk women [20]. Can CRP measurements replace the predictive value of the cumbersome FMD assessment in determining the quality of endothelial function? Apparently not, as demonstrated in a large healthy cohort of subjects in whom the predictive value of CRP was shown to be largely independent of abnormalities in endothelial function assessed by FMD testing [21].

Microalbuminuria is another laboratory parameter which is considered to be a marker of endothelial dysfunction. Whether microalbuminuria is associated with FMD has recently been investigated in an elderly population. Micro-albuminuria is linearly associated with impaired endothelium-dependent flow-mediated vasodilation in elderly individuals without and with diabetes [22]. Unfortunately, microalbuminuria, which is easy to measure, appears to be a rather late marker of endothelial dysfunction. Indeed, endothelial dysfunction, as estimated by plasma von Willebrand factor concentration, precedes and may predict the development of microalbuminuria in insulin-dependent diabetes mellitus [23].

In conclusion, up to now, no circulating factor has been convincingly shown to yield earlier and more sensitive information on endothelial function as a prognostic factor of cardiovascular events than muscarinic receptor stimulation or FMD.

Endothelial Function and Atherosclerosis

As mentioned in the previous section, endothelial dysfunction represents the primary event in atherogenesis. We have described above the different methods currently used for the in vivo assessment of endothelial function. In this section we present some of the main mechanisms linking endothelial dys function to atherosclerosis. Endothelial cells are the target of local and systemic injuries. Among the systemic factors that affect endothelium homeostasis, hyperlipidemia, diabetes mellitus, hypertension and smoking represent the most prevalent conditions in clinical settings. The initial description of the endothelium-derived vasodilator agent by Furchgott and Zawadski [24] later identified as NO occupies a key position in the pathogenesis of atherosclerosis. NO was first described as a vasodilator whose production can be controlled by different physiological agonists as well as by pharmacological agents acting on the endothelial isoform of the NO synthase (eNOS or NOSIII) gene. NO not only regulates vascular tone by directly acting on smooth muscle cells, but it also counterbalances the action of other vasoconstrictors such as endothelin-1 (ET-1) [25] and angiotensin II (Ang II) [26]. In addition, NO limits recruitment of leukocytes, inhibits platelet adhesion and aggregation, inhibits smooth muscle cells proliferation and tissue factor production [27]. Although not limited to NO metabolism, endothelium homeostasis is greatly dependent on the NO-balanced release because of the pleiotropic actions NO exerts in controlling most of the other endothelial factors. Reduced NO bioavailability is the common denominator of endothelial dysfunction associated with cardiovascular risk factors.

Most of these cardiovascular risk factors are associated with an increased production of reactive oxygen species (ROS), such as the superoxide radicals which in turn reduce vascular NO bioavailability [28]. Superoxide radicals can react with NO released by endothelial nitric oxide synthase (eNOS), thereby generating peroxynitrite. A vicious circle can then be initiated where the anti-atherosclerotic NO-producing enzyme is converted into an enzyme (uncoupling) that may trigger or even accelerate the atherosclerotic process by producing superoxide rather than NO. Therefore, reducing ROS and improving eNOS activity to increase NO bioavailability represents the mainstay of the management of cardiovascular risk factors in primary and secondary prevention.

Low-grade inflammation has been shown to contribute to atherogenesis. Leukocyte recruitment and monocyte adhesion on the activated endothelium represent one of the earliest responses in the inflammatory process associated with atherosclerosis [29]. Complex interactions exist between cytokines, che-mokines, and inflammation in the development of atherosclerosis. However, cardiovascular hormones directly involved in the control of hemodynamics and volume homeostasis may also play a crucial role in the initiation and the development of atherosclerotic plaques. We have recently demonstrated the pressure independent role of an activated renin-angiotensin-aldosterone system on atherosclerotic plaque development and vulnerability [30]. To study the contribution of Ang II in plaque vulnerability, hypertensive hypercholesterol-

Fig. 1. Atherosclerotic plaque, mean blood pressure (MBP) and serum interleukin-6 (IL-6) in ApoE knockout (ApoE KO) mice: sham is compared to high-renin and low-renin animals. K = Kidney; C = clip; PRC = plasma renin concentration. * p < 0.05 versus sham; ** p < 0.05 versus 1K1C.

emic ApoE-/- mice were generated with either normal or endogenously increased Ang II production (renovascular hypertension models) (fig. 1). Hypertensive high Ang II ApoE-/- mice developed unstable plaques, whereas in hypertensive normal Ang II ApoE-/- mice, plaques showed a stable phenotype. Vulnerable plaques from high Ang II ApoE-/- mice had a thinner fibrous cap, larger lipid core, and increased macrophage content than even more hypertensive but normal Ang II ApoE-/- mice. Our findings suggest that Ang II via the AT1 receptor, within the context of hypertension and hypercholesterolemia, independently from its hemodynamic effect behaves as a local modulator of atherosclerotic plaque phenotype probably via a T-helper cells switch. The exact role of the AT2 receptor in the proatherogenic process remains to be further clarified since recent data have demonstrated contradictory results [31, 32] .

Mechanical Stress and Endothelial Function

It is well established that endothelial dysfunction can be demonstrated quite early in the setting of cardiovascular risk factors such as hypercholester-olemia, hypertension, diabetes mellitus, and chronic smoking. However, despite the systemic effects of these cardiovascular risk factors, atherosclerosis is a focal disease which clearly shows a non-random distribution within the arterial vasculature [33]. Plaques persistently occur at definite sites such as branch points and curved areas of conduit arteries [34]. The clinical manifestations of atherothrombotic complications are determined by the non-random localization of atherosclerotic plaques. Strong evidence suggests that fluid dynamics and mechanical forces play a critical role in the initiation and the focal distribution of atherosclerotic lesions [35, 36].

Mechanical forces affecting the endothelial cells during the cardiac cycle can be distinguished in two types. The first is parallel to the flow direction. It is due to the frictional forces generated by the viscous fluid on the luminal surface of blood vessels, we therefore talk about shear stress. The second force is due to the cyclic strain and is known as circumferential stretch. It is perpendicular to the vessel wall. Circumferential stretch is a critical parameter for smooth muscle cells while it has been shown to play a minor role on the endo-thelium when combined with near physiological flow conditions (mean shear stress of 10 dyn/cm2) [37]. Conversely, several reports have demonstrated that cyclic strain mediates a significant endothelial response in the absence of flow and/or when supraphysiological strain conditions (10-20% strain) are applied [38]. Similarly, endothelial cell activation can be observed when cells are acutely submitted to cyclic strain from resting culture conditions.

Therefore, in this section we will mainly focus on shear stress, the tangential drag force which appears to be the predominant mechanical stimulus inducing changes in structure and function of endothelial cells. Early experiments were performed in in vitro flow models to study fluid dynamics along the different carotid bulb sections and revealed that low shear stress zones matched arterial surface alterations observed in cadaveric arteries. Regions exposed to low mean and oscillatory (bidirectional) shear stress were found to be prone to develop atherosclerotic lesions. These observations are somehow in opposition with those made in animal models where endothelial lesions were demonstrated in regions exposed to high shear stress induced by lumen reduction [39] but corroborate data obtained in more physiological atherosclerosis animal models [40]. The latter confirmed that low shear stress zones with cyclic reversal flow direction are prone to develop early atherosclerotic transformations. Therefore, it became manifest that disturbed blood flow plays a critical role in determining plaque location. Because it is quite difficult to study individual hemodynamic effects on endothelial functions in animal models, owing to the redundant biofeedback systems, several in vitro models mimicking physiological blood flow conditions were developed. Our laboratory has played a seminal role in this development by proposing to study the effect of combined and controlled hemodynamic parameters on different endothelial cells seeded on tubular structures with biomechanical properties similar to those of native arteries. Primary as well as endothelial cell lines have been studied to better appreciate the mechanisms by which endothelial cells sense and respond to changes in shear stress, cyclic strain, and hydrostatic pressure [37, 41, 42].

Like other laboratories, we were able to show that shear stress has a profound effect on endothelial cell cytoskeletal proteins. Endothelial cells respond in a dose-dependent manner to the increase in shear stress by reorganizing their stress fibers and by releasing atheroprotective factors or by reducing ath-erogenic mediators. Stress fibers are aligned in parallel to the flow direction and perpendicular to the circumferential strain and the Rho-ROCK pathway plays a critical role in the flow-induced rearrangement of the stress fibers [43]. The effects observed using the in vitro flow modulation were in total accordance with the observations made by Nerem et al. [44] using animal models of flow disturbances.

For a given mean shear stress value, we showed that pulsatile shear stress exerts a greater influence on endothelial cells than a constant shear stress [42]. Because endothelial cells in vivo are subjected to concomitant shear stress and cyclic strain, acting in perpendicular directions, a time lag between flow and pressure waves generated by wave reflection may influence cell function. Indeed, asynchronous shear stress and circumferential strain were demonstrated to induce an atherogenic profile of eNOS, ET-1 and COX-2 [45]. These results emphasize the importance of local hemodynamic conditions on the localization and initiation of atherosclerosis.

As mentioned earlier, increased production of ROS, such as the superoxide radicals, leads to decreased NO vascular bioavailability, thus promoting atherosclerosis. Shear stress modulates the redox state of the endothelial cells [46]. We demonstrated that the pulsatility of flow, but not cyclic stretch, was a critical determinant of flow-induced superoxide anion production [42]. p22phox mRNA levels increased in cells exposed to both unidirectional and oscillatory shear stress, suggesting that p22phox gene expression upregulation contributes to flow-induced increase in superoxide anion production in endo-thelial cells. Different results were obtained in absence of pulsatility but do not correspond to the in vivo situation and therefore should be interpreted with limitation [47]. Agents that block the renin-angiotensin system (ACE-I and ARBs) [48, 49] and statins [50] have been shown to favorably influence oxidative stress by reducing or suppressing NADPH oxidase activity independently from their primary therapeutic effect.

Shear stress does appear to have a favorable effect on inflammation. Indeed, endothelial cells release a number of factors that prevent atherogenesis such as NO, prostacyclin and SOD, to name a few that counteract inflammatory stimuli. Physiologic flow conditions have a positive impact by turning on atheroprotective genes and by turning off genes that contribute to atherosclerosis initiation or progression (adhesion molecules). Recently, Berk and colleagues [51] demonstrated that preconditioning of endothelial cells by steady laminar flow decreased apoptosis and reduced TNF-mediated endothelial cell activation by inactivation of the MAPK cascade. All these in vitro results must be interpreted bearing in mind that cells are not exposed to the full physio-pathological array of conditions such as hyperlipidemia and increased oxida-tive stress that are normally found in the in vivo situation.

Nitric Oxide and Age-Related Changes in Stiffness

Arterial stiffness is frequently considered to result mainly from the distending pressure and from the quality/quantity of elastic and collagen fibers arterial media content. However, the media is rich in smooth muscle cells that respond actively to sympathetic activation and to the paracrine release of va-somediators such as NO, ET-1 and prostacyclin to name a few. Therefore, it is not surprising that alterations in NO bioavailability influences arterial stiffness [52]. There are different ways to assess arterial elasticity. Pulse pressure which is a surrogate of large artery stiffness has been shown to be a strong in dependent predictor of the endothelial response to muscarinic receptor agonists in normotensive subjects [ 53]. Similar results have been obtained in healthy subjects and in patients with coronary artery disease in whom an inverse correlation was observed between the degree of arterial stiffness and impaired endothelial function [54].

Recently, it has become evident that for any given mean blood pressure level, aging is accompanied by vascular wall stiffening which induces opposite hemodynamic effects on blood pressure [55]. Systolic blood pressure tends to steadily increase with aging whereas diastolic blood pressure reaches a plateau around age 55-60 years before declining [56]. This trend which has been observed in most of the studied populations so far clearly shows that pulse pressure, thus arterial stiffness, increases with age.

Pulse wave velocity is another measure of arterial stiffness which is a good predictor of cardiovascular outcome in various clinical settings such as hypertension, diabetes and end-stage renal disease [57, 58]. In the latter case, accumulation of asymmetrical dimethylarginine, a potent inhibitor of eNOS, may play a critical role in the development of severe arterial stiffening in combination with media calcification due to hyperphosphatemia [59]. With aging of the population, new problems are emerging. It has been observed in the general population that low bone mass is associated with a higher mortality rate due to atherosclerotic cardiovascular disease. The degree of aortic calcification is strongly related with a lower bone mineral density. Therefore, one may speculate that low bone mineral density is a predictor of increased arterial stiffness [60, 61]. Patients with chronic renal failure also present with renal osteodystrophy. Preliminary data tend to support that pulse wave velocity is related to the severity of osteodystrophy in ESRD patients and with osteoporosis in the general elderly population [62]. To which extent endothelial dysfunction contributes to large artery stiffening with time remains to be fully addressed. Studies have looked at the acute effect of NO blockade in healthy volunteers showing an increased arterial stiffness [52]. To discriminate the effect of blood pressure increase from that of the inhibition of NO release vasoconstricting agents such as noradrenaline and dobutamine were compared to L-NMMA measuring ca-rotido-femoral PVW as a marker of elastic artery stiffness in healthy volunteers. No apparent effect of NO blockade other than the pressure effect could be detected. This observation may not be true for muscular arteries where other factors than NO may play a role in modulating vascular tone. Chronic inhibition of NO synthase or clinical conditions associated with endothelial dysfunction may induce vascular remodeling which in the long run may favor development of atherosclerosis and increased left ventricular afterload.

Endothelial function is impaired with increasing age and may therefore contribute to the steady increase in arterial stiffness observed in epidemio-

logical studies. Measures aimed at controlling cardiovascular risk factors which improve endothelial function may reverse some of the age-related stiffening of the conduit arteries by influencing both on the active component of the vessel wall via smooth muscle tone and on the passive elements such as the elastic and collagen fibers and the matrix proteins.

There is now a very large body of evidence showing that endothelial dysfunction is an early marker of atherosclerotic changes. Several mechanisms are implicated in the progression of endothelial dysfunction. Some of them are modifiable and measures to limit atherosclerosis development via endothelial alteration have proven successful. Although interesting, the demonstration of an improvement in endothelial function should be taken with great caution before being considered as a valid surrogate of clinical improvement. Indeed, recent clinical trials have demonstrated a discrepancy between improved en-dothelial function following estrogen, COX-2 inhibitors or vitamin treatment and increased cardiovascular events [63, 64].


1 Vanhoutte PM: Endothelium and control of vascular function. State of the art lecture. Hypertension 1989;13:658-667.

2 Rubanyi GM: The role of endothelium in cardiovascular homeostasis and diseases. J Cardiovasc Pharmacol 1993;4:S1-S14.

3 Ganz P, Vita JA: Testing endothelial vasomotor function. Circulation 2003; 108:2049-2053.

4 Schachinger V, Britten MB, Zeiher AM: Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 2000; 101:1899-1906.

5 Vita JA, Keaney JF Jr: Endothelial function: a barometer for cardiovascular risk? Circulation 2002;106: 640-642.

6 Suwaidi JA, Hamasaki S, Higano ST, et al: Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation 2000; 101: 948-954.

7 Halcox JP, Schenke WH, Zalos G, et al: Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002;106:653-658.

8 Lerman A, Zeiher AM: Endothelial function: cardiac events. Circulation 2005;111:363-368.

9 Kuvin JT, Patel AR, Sliney KA, Pandian NG, Rand WM, Udelson JE, Karas RH: Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. J Am Coll Cardiol 2001;38:1843-1849.

10 Zeiher AM, Drexler H, Wollschlager H, Just H: Modulation of coronary vasomotor tone in humans. Progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991;83:391-401.

11 Panza JA, Quyyumi AA, Callahan TS, Epstein SE: Effect of antihypertensive treatment on en-dothelium-dependent vascular relaxation in patients with essential hypertension. J Am Coll Cardiol 1993;21:1145-1151.

12 Sinoway LI, Hendrickson C, Davidson WR Jr, Prophet S, Zelis R: Characteristics of flow-mediated brachial artery vasodilation in human subjects. Circ Res 1989;64:32-42.

13 Hayoz D, Drexler H, Münzel T, Hornig B, Zeiher AM, Just H, Brunner HR, Zelis R: Flow mediated arterial dilation is abnormal in congestive failure. Circulation 1993;87(suppl VII):VII-92-VII-96.

14 Corretti MC, Anderson TJ, Benjamin EJ, et al: Guidelines for the ultrasound assessment of en-dothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002;39: 257-265.

15 Hayoz D, Weber R, Rutschmann B, Darioli R, Burnier M, Waeber B, Brunner HR: Post-ischemic blood flow response in hypercholesterolemic patients. Hypertension 1995;26:497-502.

16 Bonetti PO, Pumper GM, Higano ST, Holmes DR Jr, Kuvin JT, Lerman A: Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 2004;44:2137-2141.

17 Morris SJ, Shore AC: Skin blood flow responses to the iontophoresis of acetylcholine and sodium nitroprusside in man: possible mechanisms. J Physiol 1996;496:531-542.

18 De Jongh RT, Serne EH, Ijzerman RG, de Vries G, Stehouwer CD: Impaired microvascular function in obesity: implications for obesity-associated microangiopathy, hypertension, and insulin resistance. Circulation 2004;109:2529-2535.

19 Ijzerman RG, de Jongh RT, Beijk MA, van Weissenbruch MM, Delemarre-van de Waal HA, Serne EH, Stehouwer CD: Individuals at increased coronary heart disease risk are characterized by an impaired microvascular function in skin. Eur J Clin Invest 2003;33:536-542.

20 Cushman M, Arnold AM, Psaty BM, Manolio TA, Kuller LH, Burke GL, Polak JF, Tracy RP: C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. Circulation 2005;112:25-31.

21 Verma S, Wang CH, Lonn E, Charbonneau F, Buithieu J, Title LM, Fung M, Edworthy S, Robertson AC, Anderson TJ, FATE Investigators: Cross-sectional evaluation of brachial artery flow-mediated vasodilation and C-reactive protein in healthy individuals. Eur Heart J 2004;25:1754-1760.

22 Stehouwer CD, Henry RM, Dekker JM, Nijpels G, Heine RJ, Bouter LM: Microalbuminuria is associated with impaired brachial artery, flow-mediated vasodilation in elderly individuals without and with diabetes: further evidence for a link between microalbuminuria and endothe-lial dysfunction - the Hoorn Study. Kidney Int Suppl 2004;92:S42-44.

23 Stehouwer CD, Fischer HR, van Kuijk AW, Polak BC, Donker AJ: Endothelial dysfunction precedes development of microalbuminuria in insulin-dependent diabetes mellitus. Diabetes 1995; 44:561-564.

24 Furchgott RF, Zawadski JV: The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373-376.

25 Schiffrin EL, Touyz RM: Vascular biology of endothelin. J Cardiovasc Pharmacol 1998;32(suppl 3):S2-S13.

26 Dimmeler S, Rippmann V, Weiland U, Haendeler J, Zeiher AM: Angiotensin II induces apopto-sis of human endothelial cells. Protective effect of nitric oxide. Circ Res 1997;81:970-976.

27 Chen XL, Tummala PE, Olbrych MT, Alexander RW, Medford RM: Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. Circ Res 1998;83:952-959.

28 Munzel T, Daiber A, Ullrich V, Mulsch A: Vascular consequences of endothelial nitric oxide syn-thase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. Arterioscler Thromb Vasc Biol 2005;25:1551-1557.

29 Libby P, Theroux P: Pathophysiology of coronary artery disease. Circulation 2005;111:3481-3488.

30 Mazzolai L, Duchosal MA, Korber M, Bouzourene K, Aubert JF, Hao H, Vallet V, Brunner HR, Nussberger J, Gabbiani G, Hayoz D: Endogenous angiotensin II induces atherosclerotic plaque vulnerability and elicits a Th1 response in ApoE-/- mice. Hypertension 2004;44:277-282.

31 Johansson ME, Wickman A, Fitzgerald SM, Gan LM, Bergstrom G: Angiotensin II, type 2 receptor is not involved in the angiotensin II-mediated pro-atherogenic process in ApoE-/- mice. J Hypertens 2005;23:1541-1549.

32 Iwai M, Chen R, Li Z, Shiuchi T, Suzuki J, Ide A, Tsuda M, Okumura M, Min LJ, Mogi M, Horiu-chi M: Deletion of angiotensin II type 2 receptor exaggerated atherosclerosis in apolipoprotein E-null mice. Circulation 2005;112:1636-1643.

33 Cornhill JF, Herderick EE, Stary HC: Topography of human aortic sudanophilic lesions. Monogr Atheroscler 1990;15:13-19.

34 DeBakey ME, Lawrie GM, Gleaser DH: Patterns of atherosclerosis and their surgical significance. Ann Surg 1985;201:115-131.

35 Pohl U, Holtz J, Busse R, Bassenge E: Crucial role of endothelium in the vasodilator response to increased flow in vivo. Hypertension 1986;8:37-47.

36 Langille BL, O'Donnell F: Reduction in arterial diameter produced by chronic decreases in blood flow are endothelium-dependent. Science 1986;231:405-407.

37 Ziegler T, Silacci P, Harrison VJ, Hayoz D: Nitric oxide synthase expression in endothelial cells exposed to mechanical forces. Hypertension 1998;32:351-355.

38 Okada M, Matsumori A, Ono K, Furukawa Y, Shioi T, Iwasaki A, Matsushima K, Sasayama S: Cyclic stretch upregulates production of interleukin-8 and monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 in human endothelial cells. Arterioscler Thromb Vasc Biol 1998;18:894-901.

39 Fry DL: Acute vascular endothelial changes associated with increased blood velocity gradients. Circ Res 1968;22:165-192.

40 Bassiouny HS, Zarins CK, Kadowaki MH, Glagov S: Hemodynamic stress and experimental aor-toiliac atherosclerosis. J Vasc Surg 1994;19:426-434.

41 Zhao S, Suciu A, Ziegler T, Moore JE Jr, Burki E, Meister JJ, Brunner HR: Synergistic effects of fluid shear stress and cyclic circumferential stretch on vascular endothelial cell morphology and cytoskeleton. Arterioscler Thromb Vasc Biol 1995;15:1781-1786.

42 Silacci P, Desgeorges A, Mazzolai L, Chambaz C, Hayoz D: Flow pulsatility is a critical determinant of oxidative stress in endothelial cells. Hypertension 2001;38:1162-1166.

43 Lin T, Zeng L, Liu Y, DeFea K, Schwartz MA, Chien S, Shyy JY: Rho-ROCK-LIMK-cofilin pathway regulates shear stress activation of sterol regulatory element binding proteins. Circ Res 2003; 92: 1296-304.

44 Nerem RM, Levesque MJ, Cornhill JF: Vascular endothelial morphology as an indicator of the pattern of blood flow. J Biomech Eng 1981;103:172-176.

45 Dancu MB, Berardi DE, Vanden Heuvel JP, Tarbell JM: Asynchronous shear stress and circumferential strain reduces endothelial NO synthase and cyclooxygenase-2 but induces endo-thelin-1 gene expression in endothelial cells. Arterioscler Thromb Vasc Biol 2004;24:2088-2094.

46 Hojo Y, Saito Y, Tanimoto T, Hoefen RJ, Baines CP, Yamamoto K, Haendeler J, Asmis R, Berk BC: Fluid shear stress attenuates hydrogen peroxide-induced c-Jun NH2-terminal kinase activation via a glutathione reductase-mediated mechanism. Circ Res 2002;91:712-718.

47 De Keulenaer GW, Chappell DC, Ishizaka N, Nerem RM, Alexander RW, Griendling KK: Oscillatory and steady laminar shear stress differentially affect human endothelial redox state: role of a superoxide-producing NADH oxidase. Circ Res 1998;82:1094-1101.

48 Tsuda M, Iwai M, Li JM, Li HS, Min LJ, Ide A, Okumura M, Suzuki J, Mogi M, Suzuki H, Horiu-chi M: Inhibitory effects of AT1 receptor blocker, olmesartan, and estrogen on atherosclerosis via anti-oxidative stress. Hypertension 2005;45:545-551.

49 Hornig B, Landmesser U, Kohler C, Ahlersmann D, Spiekermann S, Christoph A, Tatge H, Drex-ler H: Comparative effect of ace inhibition and angiotensin II type 1 receptor antagonism on bioavailability of nitric oxide in patients with coronary artery disease: role of superoxide dis-mutase. Circulation 2001;103:799-805.

50 Pizzi C, Manfrini O, Fontana F, Bugiardini R: Angiotensin-converting enzyme inhibitors and 3-hydroxy-3-methylglutaryl coenzyme A reductase in cardiac syndrome X: role of superoxide dismutase activity. Circulation 2004;109:53-58.

51 Yamawaki H, Lehoux S, Berk BC: Chronic physiological shear stress inhibits tumor necrosis factor-induced proinflammatory responses in rabbit aorta perfused ex vivo. Circulation 2003; 108: 1619-1625.

52 Stewart AD, Millasseau SC, Kearney MT, Ritter JM, Chowienczyk PJ: Effects of inhibition of basal nitric oxide synthesis on carotid-femoral pulse wave velocity and augmentation index in humans. Hypertension 2003;42:915-918.

53 Ceravolo R, Maio R, Pujia A, Sciacqua A, Ventura G, Costa MC, Sesti G, Perticone F: Pulse pressure and endothelial dysfunction in never-treated hypertensive patients. J Am Coll Cardiol 2003; 41:1753-1758.

54 Ichigi Y, Takano H, Umetani K, Kawabata K, Obata JE, Kitta Y, Kodama Y, Mende A, Nakamura T, Fujioka D, Saito Y, Kugiyama K: Increased ambulatory pulse pressure is a strong risk factor for coronary endothelial vasomotor dysfunction. J Am Coll Cardiol 2005;45:1461-1466.

55 Sutton-Tyrrell K, Najjar SS, Boudreau RM, Venkitachalam L, Kupelian V, Simonsick EM, Havlik R, Lakatta EG, Spurgeon H, Kritchevsky S, Pahor M, Bauer D, Newman A, Health ABC Study: Elevated aortic pulse wave velocity, a marker of arterial stiffness, predicts cardiovascular events in well-functioning older adults. Circulation 2005;111:3384-3390.

56 Franklin SS, Gustin W 4th, Wong ND, Larson MG, Weber MA, Kannel WB, Levy D: Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study. Circulation 1997;96:308-315.

57 Benetos A, Adamopoulos C, Bureau JM, Temmar M, Labat C, Bean K, Thomas F, Pannier B, Asmar R, Zureik M, Safar M, Guize L: Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a 6-year period. Circulation 2002;105:1202-1207.

58 Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM: Impact of aortic stiffness on survival in end-stage renal disease. Circulation 1999;99:2434-2439.

59 Shinohara K, Shoji T, Kimoto E, Yokoyama H, Fujiwara S, Hatsuda S, Maeno T, Shoji T, Fuku-moto S, Emoto M, Koyama H, Nishizawa Y: Effect of atorvastatin on regional arterial stiffness in patients with type 2 diabetes mellitus. J Atheroscler Thromb 2005; 12:205-210.

60 Hirose K, Tomiyama H, Okazaki R, Arai T, Koji Y, Zaydun G, Hori S, Yamashina A: Increased pulse wave velocity associated with reduced calcaneal quantitative osteo-sono index: possible relationship between atherosclerosis and osteopenia. J Clin Endocrinol Metab 2003;88:2573-2578.

61 Joki N, Hase H, Shiratake M, Kishi N, Tochigi S, Imamura Y: Calcaneal osteopenia is a new marker for arterial stiffness in chronic hemodialysis patients. Am J Nephrol 2005;25:196-202.

62 Yamada S, Inaba M, Goto H, Nagata-Sakurai M, Kumeda Y, Imanishi Y, Emoto M, Ishimura E, Nishizawa Y: Associations between physical activity, peripheral atherosclerosis and bone status in healthy Japanese women. Atherosclerosis 2006;188:196-202.

63 Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N, HERS Research Group: Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.

64 Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA, Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial Investigators: Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 2005;352:1092-1102.

Daniel Hayoz

Department of Medicine, Vascular Medicine, CHUV CH-1011 Lausanne (Switzerland) Tel. +41 21 3140 750/52, Fax +41 21 3140 761 E-Mail [email protected]

Section I - Pathophysiology

Safar ME, Frohlich ED (eds): Atherosclerosis, Large Arteries and Cardiovascular Risk. Adv Cardiol. Basel, Karger, 2007, vol 44, pp 76-95

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