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(Circulation. 1997;95:357-362.)
© 1997 American Heart Association, Inc.

Articles

Mechanical Pressure and Stretch Release Endothelin-1 From Human Atherosclerotic Coronary Arteries In Vivo

David Hasdai, MD; David R. Holmes, Jr., MD; Kirk N. Garratt, MD; William D. Edwards, MD; Amir Lerman, MD

the Division of Internal Medicine and Cardiovascular Diseases, Mayo Clinic and Foundation, Rochester, Minn.

Correspondence to Amir Lerman, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN 55905.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Endothelin-1 (ET-1) is an endothelium-derived vasoactive peptide with mitogenic properties. In vitro, vascular release of ET-1 is increased in response to mechanical stress. The goal of the present study was to examine whether ET-1 is released from human atherosclerotic coronary arteries in vivo in response to mechanical pressure and stretch and to characterize immunoreactivity for ET-1 and its precursor, big ET-1, within the atheromatous plaque.

Methods and Results Circulating ET-1 levels were measured in 20 patients before and after coronary angioplasty for stable angina at three sampling sites: the femoral artery and the coronary artery segments proximal and distal to the lesion dilated. In addition, atheromatous tissue obtained from 20 patients undergoing directional coronary atherectomy for stable angina were analyzed for immunoreactivity for ET-1 and big ET-1. In patients undergoing angioplasty, ET-1 levels in the distal coronary artery increased after balloon dilatation (8.4±0.9 to 16.4±2 pg/mL, P<.05); proximal coronary artery and systemic ET-1 levels were unchanged. The degree of mechanical stress applied (product of duration and pressure of balloon inflation) correlated with the change in distal coronary artery ET-1 levels (r=.71, P<.01). Immunoreactivity for big ET-1 and ET-1 was ubiquitous in the extracellular space and the intracellular compartment (macrophages, myointimal cells, myofibroblasts, and endothelial cells) of human coronary atheromatous tissue.

Conclusions Big ET-1 and ET-1 immunoreactivity is ubiquitous within the intracellular and extracellular compartments of coronary atherosclerotic tissue. ET-1 is released from these sites in response to mechanical stress. These findings support a role for endothelins in the evolution and progression of coronary atherosclerosis in humans.

Key Words: athersclerosis • coronary circulation • endothelin • immunohistochemistry

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
ET-1 is a 21–amino acid endothelium-derived peptide cleaved from a 39–amino acid precursor, big ET-1, through proteolytic processing.^{1 2} ET-1 is a potent coronary vasoconstrictor at pathophysiological concentrations, as well as a mitogen for smooth muscle cells.^{3 4 5 6} These properties of ET-1 render it a potential mediator of coronary atherogenesis.⁷ Indeed, increased circulating and tissue ET-1 immunoreactivity levels have been reported in patients with diffuse atherosclerotic disease,⁸ as well as in animal models of early coronary atherosclerosis and coronary endothelial dysfunction.⁹

The mechanisms governing ET-1 synthesis, storage, and release in the steady state and in pathophysiological states are multifactorial.² In vitro studies have suggested that physical factors, such as shear stress,¹⁰ mechanical stretch,¹¹ and mechanical pressure,^{12 13} alter ET-1 gene expression and release by endothelial cells. However, ET-1 release in the coronary circulation in response to mechanical stress has not been demonstrated in vivo.

The present study was designed to test the hypothesis that the application of mechanical pressure and stretch on the atherosclerotic coronary vascular wall in humans results in intracoronary release of ET-1. Furthermore, our goal was to characterize ET-1 and big ET-1 immunoreactivity in the coronary atherosclerotic lesion to further our understanding of the pathophysiological basis for ET-1 in atherosclerosis.

	Methods

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The following study protocols were conducted in two phases after approval by the Mayo Clinic Institutional Review Board. All patients gave written informed consent to participate in the studies. Exclusion criteria included total coronary artery occlusion, acute or recent acute myocardial infarction, unstable angina pectoris, uncontrolled hypertension, peripheral vascular disease, heart failure, and significant endocrine, hepatic, renal, or inflammatory disease.

Phase I
This phase was designed to determine the effects of mechanical pressure and stretch on the release of ET-1 from the coronary vascular bed. Pressure is a force exerted radially at right angles to the axis of blood flow, leading to strain on the wall and secondarily causing stretch.¹² Balloon dilatation during PTCA results in exertion of mechanical pressure and stretch on the coronary vessel wall. Therefore, the PTCA procedure served as an in vivo model of mechanical pressure and stretch.

Twenty patients with stable angina who were undergoing PTCA of native vessels were studied. The decision to revascularize patients with PTCA was made by the attending cardiologist. All patients had undergone diagnostic coronary angiography 24 hours before the PTCA procedure.

The patients were brought into the cardiac catheterization laboratory in the fasting state; all cardiovascular medications had been discontinued for 12 hours. Oral aspirin (325 mg) and intravenous unfractionated heparin (15 000 U) was administered before advancement of the coronary artery guiding catheter to the aortic root (with subsequent bolus injections of heparin, if necessary, to maintain an activated clotting time of >300 seconds). Over-the-wire techniques for PTCA were used, as previously described.¹⁴ Only nonionic contrast dye was used. Balloon size–to–artery size ratios were 0.9 to 1.1 in all patients, as determined by quantitative coronary angiography.

Baseline blood samples were obtained from three sites: femoral artery and coronary artery segments proximal and distal to the site of stenosis. Blood was drawn from the femoral sheath for systemic artery samples. Coronary artery samples were obtained in the following manner: The balloon catheter was advanced 2 cm distal to the stenosis, the guide wire was withdrawn, and a blood sample was obtained through the balloon catheter. The guide wire was reloaded, the balloon catheter was withdrawn to 2 cm proximal to the site of stenosis, and a sample was obtained. After the lesion had been dilated, blood samples were obtained from the same three sites. For each inflation of the balloon catheter, the maximal pressure and total time of inflation were recorded.

The cineangiography films were reviewed by two investigators. A manual edge-detection system was used to determine luminal diameter stenosis before and after the PTCA procedure.

Plasma ET-1 was determined by the ET-1,2[¹²⁵I] assay system from Amersham, as we previously described.⁷ Blood was drawn into tubes containing chilled potassium EDTA and immediately placed on ice until it was centrifuged at -4°C. Plasma was separated and frozen at -20°C until the assay. Before the radioimmunoassay, plasma was acidified with 0.5% TFA. C8 Bond Elut cartridges were washed with 4 mL of methanol and 4 mL of water to extract the plasma. After the plasma was applied, cartridges were washed with 2 mL of normal saline and 6 mL of water. Endothelin was eluted from the cartridges with 2 mL of 90% methanol in 1% TFA and then dried and reconstituted for the radioimmunoassay. Recovery of the extraction procedure was 81% as determined by the addition of synthetic endothelin to plasma, and interassay and intra-assay variations were 9% and 5%, respectively. The minimal level of detection was 0.5 pg per tube. The cross-reactivity of ET-2, ET-3, and proendothelin in this assay was <5%, <3%, and <37%, respectively.

To further ensure that changes in coronary levels of ET-1 do not represent generalized activation of vasoactive peptides and do not merely reflect changes in coronary blood flow, plasma concentrations of atrial natriuretic peptide were obtained from all three sites before and after balloon inflation with the use of a double-antibody radioimmunoassay (Peninsula Laboratories) as previously described.¹⁵

Phase II
This phase was designed to characterize and localize ET-1 and big ET-1 immunoreactivity in atheromatous human coronary arteries. Coronary artery specimens were obtained from 20 consecutive patients who underwent DCA for primary coronary artery lesions of native vessels causing stable angina pectoris. DCA was performed using the Simpson directional atherectomy device (Devices for Vascular Intervention) as previously described.¹⁶ After extraction of the atheromatous tissue, the specimens were carefully removed from the housing chamber of the catheter, washed with 0.9% saline solution, and cut into small pieces. Samples were analyzed by light microscopy, as detailed below.

Light Microscopy
Specimens obtained from DCA were fixed in 10% formalin. Paraffin sections were stained with hematoxylin and eosin and Verhoef/van Gieson for elastin and collagen to define cellular architecture. Serial unstained sections were also used for immunohistochemistry. Cell types were determined using the following specific monoclonal antibodies¹⁷ : -actin (marker for myointimal cells), vimentin (marker for mesenchymal cells, including myointimal cells and myofibroblasts), von Willebrand factor (marker for endothelial cells), and leukocyte-common antigen (marker for leukocytes, including macrophages and neutrophils).

Tissue presence of big ET-1 and ET-1 was assessed through immunohistochemistry as we previously reported.⁷ The specimens were embedded in paraffin, and 6-µm-thick sections were cut and mounted on silanized slides. The slides were incubated overnight at 60°C and deparaffinized with graded concentrations of xylene and ethanol. The slides were washed with 0.6% H₂O₂ in methanol for 20 minutes at room temperature to block endogenous peroxidase activity. They were first incubated with 5% normal goat serum for 10 minutes (Dako Co) at room temperature to reduce nonspecific background staining and then with rabbit polyclonal ET-1 and big ET-1 antiserum (Peninsula Laboratories) diluted at 1:1600 in humidified chambers for 24 hours at room temperature. There was no cross-reactivity between ET-1 and big ET-1 antisera. Control slides were treated with dilute normal rabbit serum (Dako Co). All treated slides were exposed for 30 minutes to goat anti-rabbit antiserum (Tago Inc) diluted at 1:100 to which peroxidase had been covalently linked. Peroxidase activity was visualized with 3-amino-9-ethylcabazole (Sigma Chemical Co) dissolved in dimethylformamide and sodium acetate. The sections were counterstained with hematoxylin and then mounted and reviewed with an Olympus microscope. Localization of big ET-1 and ET-1 was done by comparing these slides with those from adjacent tissue sections from the same block, stained for one of the cell markers detailed above. Immunoreactivity for big ET-1 or ET-1 within 5 cells per microscopic field in a x100 magnification was considered to be positive staining for the specific cell type.

All histopathological and immunohistochemical specimens were reviewed by an experienced cardiovascular pathologist (Dr Edwards). For each immunohistochemical analysis, control slides were prepared using normal nonimmune serum.

Statistical Analysis
ET-1 levels are presented as mean±SEM. Differences in ET-1 levels within the same group were analyzed for statistical significance using the paired Student's t test. Differences in circulating ET-1 levels between sites of sampling were evaluated using the unpaired Student's t test and ANOVA. Statistical significance was achieved at a value of P<.05.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Phase I
Twenty patients (12 men) 46 to 82 years of age were studied in this phase (Table 1). PTCA was performed in the left anterior descending coronary artery in 10 patients, in the right coronary artery in 8 patients, and in the left circumflex coronary artery in 2 patients. Demographic and clinical characteristics of the patient population are given in Table 1. There was no statistical difference in circulating ET-1 concentrations between the different sites at baseline (Table 2). However, in response to balloon dilatation, there was a significant increase in intracoronary ET-1 concentrations only in the distal coronary site (8.4±0.9 to 16.4±2 pg/mL, P<.05), (Fig 1). There also was a significant increase in ET-1 gradient across the lesion after the balloon dilatation (Table 2). A significant correlation was found between the increase in ET-1 concentrations at the distal coronary site and the degree of mechanical stress, as evaluated by multiplying the total duration of inflations (minutes) and pressure of balloon inflation (atm) (Fig 2). There was no correlation between the change in intracoronary ET-1 levels in the distal coronary artery and the balloon size, the number of inflations, or the amount of contrast medium injected.

View this table: [in this window] [in a new window]   Table 1. Demographic, Clinical, and Angiographic Profile of Patients Undergoing PTCA

View this table: [in this window] [in a new window]   Table 2. Plasma ET-1 Levels at Sampling Sites

View larger version (47K): [in this window] [in a new window]   Figure 1. ET-1 levels in the proximal (shaded bars) and distal coronary artery (striped bars) before and after PTCA (ie, proximal and distal to the site of dilatation).

View larger version (11K): [in this window] [in a new window]   Figure 2. Correlation between the mechanical stress applied on the coronary artery wall (assessed by multiplying the length of time of balloon inflation by the maximal pressure of balloon inflation) and the change in ET-1 levels in the distal coronary artery (ie, distal to the site of dilatation).

In contrast, plasma levels of atrial natriuretic peptide at the three sampling sites were not significantly different or altered by the application of mechanical stress (data not shown).

Phase II
Coronary artery tissue specimens were available from 20 patients who were undergoing DCA because of chronic stable angina pectoris. Light microscopy and immunohistochemistry for specific cell types revealed disruption of the endothelial layer, microvessel neovascularization within the vascular wall (von Willebrand factor), avid staining for -actin, and intense infiltration of the vascular wall by macrophages (leukocyte-common antigen). Areas of cellular necrosis were seen with the atheromatous plaque. Immunoreactivity for ET-1 and big ET-1 was detected in all specimens in areas with preserved cellular morphology, as well as in areas of necrosis. ET-1 immunostaining was more intense than big ET-1 (Figs 3 and 4). Big ET-1 and ET-1 immunoreactivity was present both intracellularly and extracellularly. Big ET-1 and ET-1 immunoreactivity was prominent in endothelial cells, macrophages, and fibroblasts, as well as myointimal cells (Fig 5). Control samples exposed to dilute normal rabbit serum were not stained (Fig 3).

View larger version (97K): [in this window] [in a new window]   Figure 3. Representative photomicrographs showing big ET-1 and ET-1 immunoreactivity in 6-µm sections of coronary artery atheromatous tissue obtained by DCA (magnification x100). Big ET-1 (A) and ET-1 (B) immunoreactivity, highlighted in reddish-brown, can be seen within cells, as well as in the extracellular compartment. There is no immunohistochemical brown staining in control samples exposed to normal rabbit serum (C).

View larger version (155K): [in this window] [in a new window]   Figure 4. Intracellular localization of ET-1 within a fibroblast by immunohistochemistry (magnification x250).

View larger version (44K): [in this window] [in a new window]   Figure 5. Relative distribution of big ET-1 and ET-1 immunoreactivity within the different cell types and the extracellular compartment.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The results of the present study demonstrate for the first time that ET-1 is released from the atherosclerotic coronary vasculature in response to mechanical pressure and stretch. Using immunohistochemical analysis, we found intracellular and extracellular loci of big ET-1 and ET-1 immunoreactivity within the atheromatous plaque. Physical forces may release ET-1 from these storage sites. These studies support a role for ET-1 as a mediator of the coronary vascular response to mechanical stress.

Release of ET-1
The coronary circulation is under constant exposure to mechanical forces. In response to changes in hemodynamic factors, the functional and structural properties of the arterial wall are altered.¹⁸ In particular, atheromatous plaque formation and progression within the vessel wall^{19 20} as well as vascular release of ET-1^{10 11 12 13} may be greatly influenced by physical forces.

Mechanical pressure and stretch are associated with increased ET-1 release from endothelial cells in vitro.^{11 12 13} During PTCA, mechanical pressure and stretch are applied on the vascular wall. Accordingly, circulating ET-1 levels are elevated after PTCA.^{15 21 22 23 24} Our observations extend these prior studies and demonstrate that ET-1 is released locally into the coronary circulation in response to mechanical stress. Furthermore, the release of ET-1 correlates with the degree of mechanical stress that is applied. Coronary artery levels of atrial natriuretic peptide do not rise, further attesting that the release of ET-1 does not represent a generalized nonspecific activation of vasoactive peptides and does not merely reflect the changes in coronary blood flow occurring after PTCA. We could not determine whether release of ET-1 from the coronary vasculature was derived from intracellular or extracellular stores and, if from the former, from which cell type. However, as described below, our current data, as well as those from previous studies,^{7 8 25} indicate that there are multiple storage sites for ET-1 in atherosclerotic coronary arteries other than endothelial cells from which ET-1 can be released.

The mechanism for ET-1 release in response to mechanical stress may be multifactorial. In vitro, mechanical stretch of endothelial cells results in a biphasic response of ET-1 release¹³ ; the initial release of ET-1, occurring within the first 20 minutes of exposure to mechanical stretch, is not blocked by actinomycin D (an inhibitor of mRNA transcription) or cycloheximide (an inhibitor of protein synthesis), suggesting that ET-1 is released from intracellular stores, perhaps through activation of phospholipase C and protein kinase. The latter stages of ET-1 release probably represent de novo ET-1 synthesis.¹³

Malatino and colleagues,²⁴ with serial sampling of the coronary sinus for ET-1 after PTCA, also revealed a double peak; the first peak occurred within 5 minutes of inflation, and the second peak became apparent 1 hour later. In our study, we obtained intracoronary artery samples immediately after the last inflation. Accordingly, the increase in ET-1 levels that we observed most probably represents release of ET-1 from its multiple storage sites or rapid conversion from big ET-1 to ET-1. It is less likely that at this time frame, de novo synthesis of ET-1 had occurred.

Application of mechanical stress on the coronary arterial wall during PTCA causes vascular injury. In response to vascular injury, the genotypic and phenotypic properties of the vascular wall are altered. ET-1 has been implicated as a major mediator of the events occurring after vascular injury,^{4 5 6} although release of ET-1 after vascular injury has not been proved. In our study, it is likely that injury to the vascular wall incurred during PTCA, and the ensuing acute intracellular and extracellular changes contributed to the release of ET-1. Therefore, for mechanical stress to cause release of ET-1 from the coronary vascular bed, a certain degree of vascular injury may be exigent.

Clinical Implications
PTCA is associated with abnormal coronary vasomotor changes, which are evident during the procedure but persist for hours or days after the acute intervention.^{26 27 28 29 30} These vasomotor changes are presumed to result from the release of vasoactive humoral agents and neurosympathetic activation. Fischell and coworkers²⁸ demonstrated that distal coronary vasoconstriction after PTCA most probably results from pressure/stretch–dependent mechanisms. ET-1 at low doses causes significant vasoconstriction of the epicardial vessels, as well as the coronary microcirculation, and consequently causes myocardial ischemia.^{3 31 32} Atherosclerosis increases the sensitivity of arteries to endothelins, resulting in an enhanced vasoconstrictor response to ET-1.³³ Therefore, it is reasonable to attribute some of the coronary hemodynamic changes associated with PTCA to ET-1 release from the coronary vasculature through pressure/stretch–dependent mechanisms. In the long term, release of ET-1 from its storage sites may accelerate smooth muscle proliferation after PTCA and as a result enhance the process of restenosis.^{4 5 6}

The results of the present study have clinical ramifications that extend beyond coronary interventional procedures. Atherosclerotic plaques tend to form in regions of low shear stress.^{19 20} However, the turbulent flow that results from narrowing of the arterial lumen by the atheromatous plaque and the strong pulsatile flow associated with atherosclerosis can exert pressure and, ultimately, a stretch effect on the vascular wall.³⁴ As shown in the present study, these mechanical forces can cause release of ET-1 from its storage sites. In turn, ET-1 that is released from atherosclerotic vessels can affect systemic and local hemodynamics as a vasoconstrictor^{2 3} and can accelerate atherogenesis as a mitogenic growth factor.⁹ Agents that lower blood pressure, such as ß-adrenergic antagonists, calcium channel blockers, and ACE inhibitors, might exert their antihypertensive and antiatherogenic effects,^{35 36 37 38} in part by blunting the pressure and stretch exerted on the atherosclerotic vascular wall, and thus attenuating the release of ET-1. Indeed, it has been shown that ACE inhibitors can attenuate circulating ET-1 levels in essential hypertension,³⁹ perhaps through inhibition of ET-1 release.^{40 41}

ET-1 Immunoreactivity Within the Atheromatous Plaque
We previously reported that a high-cholesterol diet in pigs for 4 months resulted in coronary artery ET-1 immunoreactivity in endothelial cells as well as in the subendothelial myointimal cells and/or macrophages; there was no detectable coronary artery ET-1 immunoreactivity in pigs that were fed a normal diet.⁷ In humans with diffuse atherosclerosis, ET-1 immunoreactivity was detected in both intracellular and extracellular components of the aorta vascular wall.⁸ Others²⁵ demonstrated ET-1 immunoreactivity in atherectomy specimens obtained from patients with stable and unstable angina. The authors presumed that extracellular ET-1 was derived from previously injured or dead cells.²⁵ The present results extend these previous observations and demonstrate the presence of the precursor, big ET-1, in the atherosclerotic tissue, suggesting local production and secretion of the peptide.

In the present study, we detected ET-1 immunoreactivity within several cell types, including macrophages, myointimal cells, myofibroblasts, and endothelial cells, in patients with stable angina pectoris. In addition, we found big ET-1 immunoreactivity in these sites, albeit to a lesser extent. In contrast to Zeiher and colleagues,²⁵ we detected extracellular immunoreactivity for big ET-1 and ET-1 in nonnecrotic regions. The origin of the extracellular big ET-1 and ET-1 was not determined in our study. However, it has previously been reported that ET-1 release by endothelial cells is primarily abluminal to the basement membrane and extracellular space.⁴² Furthermore, other cell types that are abundant in the atheromatous plaque, such as macrophages, smooth muscle cells, and fibroblasts, can also secrete big ET-1 and ET-1 in response to different stimuli.^{43 44 45} Thus, it is possible that the presence of ET-1 in the extracellular space is of pathophysiological significance and does not merely reflect spillover from damaged cells.

The ubiquitous presence of ET-1 in the extracellular space of atherosclerotic coronary arteries suggests that it contributes to the structural and functional changes characteristic of the atherosclerotic lesion. The extracellular matrix undergoes functional and structural changes in response to injury or inflammation, which may be mediated to a great extent by ET-1 through activation of protein kinase C.⁴⁶ ET-1 also increases collagen synthesis by fibroblasts and reduces collagenase activity.⁴⁷ In addition, ET-1, along with other growth factors stored in the extracellular space of atherosclerotic coronary arteries, such as basic fibroblast growth factor,⁴⁸ may mediate extracellular matrix contraction⁴⁶ and thus contribute to adverse remodeling of the coronary artery.

Our analysis of tissue specimens obtained during DCA underscores two important facets of vascular ET-1 metabolism in atherosclerosis. Local ET-1 levels may be regulated to a great extent by exogenous cells that infiltrate the vascular wall (ie, macrophages) and participate in atherogenesis. In addition, the extracellular space is a significant reservoir for big ET-1 and ET-1; ET-1 may be released from this reservoir by forces that do not affect cellular mechanisms and signal transduction. Thus, release of ET-1 from atherosclerotic arteries might be very much different from unaffected vessels.

Conclusions
The present study demonstrates that in humans, there are intracellular and extracellular loci of big ET-1 and ET-1 immunoreactivity within coronary atherosclerotic tissue. ET-1 is released from the atherosclerotic coronary vasculature in response to mechanical stress. These findings support a role for endothelins in the evolution of altered coronary vascular reactivity and coronary artery remodeling in the course of coronary artery atherogenesis.

	Selected Abbreviations and Acronyms

 

DCA = directional coronary atherectomy ET-1 = endothelin PTCA = percutaneous transluminal coronary angioplasty TFA = trifluoroacetic acid

	Acknowledgments

 
This study was supported by grants from the National Institutes of Health (HL-03180-01); American Heart Association, Minnesota Affiliate; and the Mayo Foundation. Dr Hasdai is a recipient of a fellowship from the American Physicians Fellowship for Medicine in Israel. We thank Dr John C. Burnett, Jr, and Linda J. McKinley for their invaluable assistance in carrying out this project.

Received May 1, 1996; revision received August 5, 1996; accepted August 28, 1996.

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