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(Hypertension. 1997;29:683-689.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Chronic Arterial Hypertension on Constitutive and Induced Intercellular Adhesion Molecule-1 Expression In Vivo
the Department of Physiology, LSU Medical Center, Shreveport, La (S.K., J.P., J.M.R., D.N.G.); Discovery Research, Upjohn Laboratories, Kalamazoo, Mich (D.C.A.); Institute for Environmental Medicine, University of Pennsylvania, Philadelphia (V.R.M.); and Department of Bioregulation, Biomedical Research Center, Osaka (Japan) University Medical School (M.M.).
Correspondence to D. Neil Granger, PhD, Department of Physiology, LSU Medical Center, 1501 Kings Hwy, Shreveport, LA 71130-3932. E-mail dgrang@lsumc.edu
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Abstract |
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Recent reports indicate that bacterial endotoxin (lipopolysaccharide) and cytokines elicit a more profound increase in the surface expression of intercellular adhesion molecule-1 (ICAM-1) in cultured endothelial cells derived from spontaneously hypertensive (SHR) versus normotensive Wistar-Kyoto rats (WKY). Our objective in this study was to characterize and compare in vivo ICAM-1 expression in SHR and WKY under basal conditions and after 5 hours of endothelial cell activation with either lipopolysaccharide (5 mg/kg IP) or tumor necrosis factor-
(TNF-; 1, 5, and 10 µg/kg IP). ICAM-1 expression was quantified in different tissues by the double-radiolabeled monoclonal antibody technique. When constitutive (baseline) ICAM-1 expression was corrected for endothelial cell surface area, significantly higher values were noted in SHR than WKY but only in splanchnic organs. Lipopolysaccharide and TNF- elicited significant increases in ICAM-1 expression in all tissues of both WKY and SHR. However, the magnitude of the lipopolysaccharide-induced ICAM-1 upregulation in heart, stomach, skeletal muscle, and brain was significantly lower in SHR than WKY. A similar blunted ICAM-1 upregulation was noted in the stomach of SHR after administration of 5 µg/kg TNF-. The differences in induced ICAM-1 expression between SHR and WKY do not appear to be due to differences in endothelial cell surface area or plasma glucocorticoid levels. These results suggest that chronic arterial hypertension results in altered ICAM-1 expression on the endothelium, which may contribute to the abnormal inflammatory responses associated with this disease.
Key Words: endothelium • rats, inbred SHR • angiotensin-converting enzyme • tumor necrosis factor- • lipopolysaccharide • glucocorticoid
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Introduction |
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The adhesion of leukocytes to vascular endothelial cells (LECA) is a critical early step in the development of an inflammatory response.1 2 3 The process of LECA is coordinated by complex interactions between surface glycoproteins on leukocytes and their corresponding counterreceptors on endothelial cells. The ß2 subfamily of integrins (CD18) are expressed on leukocytes4 5 and bind to glycoproteins of the immunoglobulin superfamily, such as ICAM-1 and ICAM-2, which are expressed on vascular endothelium.6 7 Both ICAM-1 and ICAM-2 are constitutively expressed on the surface of endothelial cells grown in culture. Stimulation of endothelial cell monolayers with either endotoxin or cytokines leads to increased ICAM-1 expression,8 which results in an increased binding of neutrophils and lymphocytes to endothelial cells.9
Although leukocyte adhesion to endothelial cells is essential for host defense and repair, it is now recognized that adherent leukocytes can also mediate the endothelial cell injury and microvascular dysfunction that are associated with a number of cardiovascular diseases, including ischemic disorders10 11 12 and atherogenesis.13 Recent reports indicate that some of the risk factors for cardiovascular diseases such as hypertension,14 15 diabetes,16 and hypercholesterolemia17 can exert a profound influence on the adhesive interactions between activated leukocytes and vascular endothelial cells. For example, the results of in vitro studies indicate that endotoxin- or cytokine-stimulated ICAM-1 expression14 and monocyte adhesion15 occur more intensely on endothelial cells derived from SHR than cells from normotensive WKY, suggesting that endothelial cells exposed to chronic arterial hypertension may sustain a higher level of leukocyte adhesion than their normotensive counterparts. However, these observations appear to be inconsistent with in vivo studies that demonstrate blunted LECA interactions elicited by platelet-activating factor, leukotriene B4, 18 or histamine19 20 in SHR compared with WKY.
Recently, a novel approach for in vivo quantification of endothelial cell adhesion molecule expression was developed based on the use of dual radiolabeled mAbs.21 Since this technique appears to detect ICAM-1 expression with a precision not previously attained by histochemical procedures, it represents a potentially powerful tool for assessment of the factors that regulate ICAM-1 expression in various pathological conditions. Hence, we used the dual radiolabeled mAb technique in the present study to characterize and compare in vivo ICAM-1 expression in SHR and WKY under basal conditions and after endothelial cell stimulation with either LPS or TNF-. Since chronic hypertension may lead to anatomic changes in microvessel density and endothelial cell surface area,22 23 24 we used a radiolabeled mAb directed against ACE, which is expressed on the luminal surface of vascular endothelium, to determine whether SHR and WKY exhibit differences in endothelial cell surface area on a per gram tissue basis.
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Methods |
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Monoclonal Antibodies
The mAbs used for the in vivo assessment of ICAM-1 expression were 1A29, a mouse IgG1 against rat ICAM-125 ; P-23, a nonbinding murine IgG1 directed against human P-selectin26 ; CL26, a mouse IgG1 against rat CD1827 ; and 9B9, a mouse IgG1 directed against human ACE that cross-reacts with rat and monkey ACE.28 MAbs 1A29, P-23, and CL26 were scaled up and purified by protein A-G chromatography (Pharmacia & Upjohn). Dr Sergey M. Danilov generously provided mAb 9B9.
Radioiodination of mAbs
The binding mAbs directed against either ICAM-1 (1A29) or ACE (9B9) were labeled with 125I (DuPont-NEN), and the nonbinding mAb (P-23) was labeled with 131I. The chloramine T method29 was used for labeling mAbs 1A29 and P-23. Briefly, a 1-mg aliquot of mAb in 1.5 mL sodium phosphate buffer (pH 7.4) was added to 125I or 131I, with a total activity of 1.0 mCi, and 100 µg chloramine T. The mixture was incubated for 1 minute at room temperature, and 62.5 µg sodium metabisulfite was added. Radioiodination of mAb 9B9 with 125I was performed by the iodogen method,30 which was also used for labeling of 1A29 in the aortic expression studies. Briefly, 250 µg protein was incubated with 250 µCi sodium 125I and 125 µg iodogen at 4°C for 12 minutes. After radioiodination by either the chloramine T or iodogen method, the radiolabeled mAbs were separated from free 125I by gel filtration on a Sephadex PD-10 column (Pharmacia LKB). The column was equilibrated with phosphate buffer containing 1% bovine serum albumin and eluted with the same buffer. Two fractions of 2.5 mL each were collected, the second of which contained the labeled antibody. Absence of free 125I or 131I was ensured by extensive dialysis of the protein-containing fraction. Less than 1% of the activity of the protein fraction was recovered from the dialysis fluid. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis showed normal heavy and light chain moieties of expected molecular weights. Labeled mAbs were stored in 500-µL aliquots at 4°C and used within 3 weeks after the labeling procedure. The specific activity of labeled mAbs was 0.5 µCi/µg.
Animal Procedures
Male SHR (8 to 10 weeks old, n=78) and age-matched WKY (n=78) weighing 200 to 240 g were obtained from Harlan Laboratories (Frederick, Md). Anesthesia was induced by intraperitoneal injection of thiobutabarbital (Inactin, RBI) at a dose of 120 mg/kg body wt. A tracheostomy was performed on each rat to facilitate breathing throughout the experiment, and the right carotid artery and right jugular vein were cannulated. Systemic arterial pressure was measured with a Statham P23A pressure transducer and recorded with a Grass polygraph D.C. driver amplifier. For measurement of ICAM-1 expression, a mixture of 5 µg 125I–ICAM-1 mAb (1A29), 5 µg 131I–nonbinding mAb (P-23), and 100 µg unlabeled ICAM-1 mAb was administered through the jugular vein catheter. This dose of ICAM-1 mAb has been shown to saturate all the relevant adhesion receptors expressed on vascular endothelial cells.21 For estimation of aortic ICAM-1 expression, 50 µg (instead of 100 µg) unlabeled ICAM-1 mAb was administered, since the binding of labeled ICAM-1 to aortic endothelium was too low for accurate estimates of surface expression with the 100-µg dose of cold mAb. An increased TNF-–induced ICAM-1 expression was readily detected with the lower dose of cold mAb, indicating levels sufficient to saturate ICAM-1 aortic endothelium.
We recently reported that the binding of an ACE-specific mAb (9B9) on vascular endothelium is well correlated with morphological estimates of endothelial surface area in different tissues.31 Hence, in some experiments on SHR and WKY, estimates of tissue endothelial surface area were obtained via administration of a mixture of 5 µg 125I-9B9 mAb, 5 µg 131I–P-23, and 25 µg unlabeled 9B9 through the jugular vein catheter. Blood samples were obtained through the carotid artery catheter at 2.5 and 5 minutes after injection of the mAb mixture. Thereafter, the rats were heparinized (1 mg/kg sodium heparin) and rapidly exsanguinated by vascular perfusion with sodium bicarbonate buffer via the jugular vein and simultaneous blood withdrawal via the carotid artery. The inferior vena cava was then severed at the thoracic level, and the carotid artery was perfused with sodium bicarbonate buffer. After completion of the exchange transfusion, organs were harvested and weighed.
Calculation of ICAM-1 Expression
125I (binding mAb) and 131I (nonbinding mAb) activities in different organs and in 100-µL aliquots of cell-free plasma were counted in a gamma counter (14800 Wizard 3, Wallac), with automatic correction for background activity and spillover. The injected activity in each experiment was calculated by counting a 5-µL sample of the mixture containing the radiolabeled mAbs. The radioactivities remaining in the tube used to mix the mAbs, the syringe used to inject the mixture, and the jugular vein catheter were subtracted from the total calculated injected activity. The accumulated activity of each mAb in an organ was expressed as the percentage of the injected dose (% I.D.) per gram of tissue. The formula used for calculation of ICAM-1 expression was ICAM-1 Expression=[(% I.D./g for 125I)-(% I.D./g for 131I)x(% I.D. 125I in Plasma)]/(% I.D. 131I in Plasma). We modified this formula from the original method21 to correct the tissue accumulation of nonbinding mAb for the relative plasma levels of both binding and nonbinding mAbs. We converted this value, expressed as % I.D., to micrograms mAb per gram tissue by multiplying the above value by the total injected binding mAb (micrograms) and dividing by 100. We used an identical procedure to estimate the relative binding of mAb 9B9 and endothelial surface area in different tissues.
Experimental Protocols
To compare constitutive and LPS- and TNF-induced ICAM-1 expressions in WKY and SHR, we used the following general protocol. Constitutive ICAM-1 expression was assessed by injecting the mixture of radiolabeled (125I-1A29 and 131I–P-23) and unlabeled (1A29) mAbs into untreated rats (10 rats per group), with the tissues harvested as described above. The magnitude of endotoxin-induced ICAM-1 expression in different tissues was determined 5 hours after injection of a single dose (5 mg/kg IP) of Salmonella abortus equi LPS (Sigma Chemical Co), a dose that was recently shown to induce significant ICAM-1 expression in rats21 (8 rats per group). Dose-response characterization of ICAM-1 expression in WKY and SHR was performed with recombinant murine TNF- (1.3x105 U/µg, R&D Systems) at doses of 1, 5, and 10 µg/kg IP,32 with organs harvested 5 hours after TNF- administration (6 to 8 rats per group). In another series of experiments, the glucocorticoid receptor antagonist RU-486 (2.0 or 20 mg/kg IP) was administered 1 hour before LPS (5 mg/kg) administration in SHR and WKY. To exclude the possible influence of LPS-induced leukocyte plugging and/or intravascular coagulation on ICAM-1 binding to vascular endothelium, we pretreated some rats with 100 µg of an mAb (CL26) directed against the leukocyte adhesion molecule CD11/CD18 plus 1 U/g body wt of heparin at 5 minutes before LPS injection. Relative endothelial cell surface area per gram tissue was determined by measurement of the binding of an mAb against ACE in the microvasculature of WKY and SHR under basal conditions and after 5 hours of treatment with either LPS (5 mg/kg) or TNF- (5 µg/kg, 4 to 5 rats per group). In some experiments, ICAM-1 expression was measured in the aorta of WKY and SHR under basal conditions and 5 hours after treatment with TNF- (5 µg/kg, 5 to 6 rats per group).
Statistics
Data were analyzed by ANOVA with Scheffe's (post hoc) test. Either paired or unpaired Student's t test was used when only two groups were compared. All values are presented as mean±SE. Statistical significance was set at a value of P<.05.
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Results |
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Effects of LPS and TNF-
on ICAM-1 ExpressionICAM-1 expression increased in a dose-dependent manner after TNF-
administration in all organs studied in both WKY and SHR. ICAM-1 expression also increased in response to LPS. Pretreatment with mAb CL26 and heparin did not affect LPS-induced ICAM-1 expression in SHR (Fig 1
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Comparison of Induced ICAM-1 Expression Between WKY and SHR
Although constitutive ICAM-1 expression did not differ significantly between the two rat groups, LPS-induced ICAM-1 expression was significantly lower in SHR than WKY in all organs studied (Fig 1
). ICAM-1 expression induced by 5 µg/kg TNF- was significantly lower in SHR than WKY but only in stomach (Fig 1b). No significant differences were noted between WKY and SHR treated with either 1 or 10 µg/kg TNF- (Fig 1).
Differential Responsiveness of WKY and SHR to LPS and TNF-
The responsiveness of ICAM-1 expression to 5 mg/kg LPS, normalized relative to constitutive ICAM-1 expression, was significantly lower in SHR than WKY in heart, stomach, skeletal muscle, and brain (Fig 2). The responsiveness of ICAM-1 expression to 5 µg/kg TNF- was significantly lower in SHR than WKY but only in stomach (Fig 2). No significant differences were noted between WKY and SHR treated with either 1 or 10 µg/kg TNF-.
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Binding of mAb Against ACE
Under baseline conditions, binding of anti-ACE mAb was comparable in SHR and WKY for all organs studied except stomach, in which SHR exhibited lower mAb 9B9 binding (Fig 3). Although neither 5 mg/kg LPS nor 5 µg/kg TNF- (at 5 hours) elicited a remarkable change in mAb 9B9 in heart, skeletal muscle, or brain, a significant increase was noted in the stomach of SHR (Fig 3). Consequently, WKY and SHR exhibited comparable levels of 9B9 binding on endothelial cells of all organs studied after exposure to LPS or TNF-.
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ICAM-1 Expression Normalized for Endothelial Surface Area (ACE Expression)
When ICAM-1 expression was normalized relative to corresponding values for ACE expression in each organ of WKY and SHR, to compensate for any differences in endothelial surface area between the two groups, constitutive ICAM-1 expression was significantly higher in SHR than WKY in the stomach (Fig 4) and other splanchnic organs, such as pancreas, mesentery, and small and large intestines (data not shown).
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ICAM-1 Expression on Aortic Endothelial Cells
TNF- (5 µg/kg) significantly increased ICAM-1 expression on aortic endothelium of both WKY and SHR. However, no significant differences were noted between the two groups relative to either constitutive or TNF-–induced ICAM-1 expression (Fig 5).
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Effects of Glucocorticoid Inhibition on ICAM-1 Expression
The glucocorticoid receptor antagonist RU-486 did not affect constitutive ICAM-1 expression in the heart of either WKY or SHR at any dose studied (2 and 20 mg/kg). Although the differences in LPS (5 mg/kg)–induced ICAM-1 expression normally observed in WKY and SHR were not affected by pretreatment with 2 mg/kg RU-486, the higher dose (20 mg/kg) abolished the difference in LPS-induced ICAM-1 expression between the hearts of WKY and SHR (Fig 6). A similar pattern of ICAM-1 expression in response to RU-486 was noted in other organs (data not shown).
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Discussion |
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A growing body of evidence suggests that alterations in immune function may account for some of the end-organ injury associated with chronic arterial hypertension. Some of the manifestations of this altered immune function in hypertensive individuals and/or animal models of hypertension include an increased number of circulating leukocytes,33 34 a larger number of activated circulating granulocytes,33 35 36 37 and a blunted LECA response to in flammatory mediators.18 19 20 Inasmuch as adhesion molecules expressed on the surface of leukocytes (CD11/CD18, L-selectin) and endothelial cells (ICAM-1, P-selectin) are recognized as major determinants of the level of LECA sustained by the microvasculature, it has been proposed that the altered immune function in chronic arterial hypertension is likely to reflect an abnormal expression of these adhesion glycoproteins on the surface of circulating leukocytes and/or endothelial cells. For example, Schmid-Schonbein and associates38 have invoked a blunted expression of P-selectin on vascular endothelial cells to explain the attenuated histamine-induced recruitment of leukocytes in mesenteric venules of SHR compared with WKY. An altered expression of other endothelial cell adhesion molecules such as ICAM-1 may occur as well because lipid mediators (leukotriene B4, platelet-activating factor) that are known to promote LECA through ß2-integrin–ICAM adhesive interactions also elicit a blunted response in mesenteric venules of SHR compared with WKY.18 However, the possibility that an altered ICAM-1 expression on SHR endothelial cells may explain the latter findings is not consistent with studies performed on cultured endothelial cells harvested from either SHR or WKY, in that SHR endothelial cells exhibit a higher level of ICAM-1 expression in response to LPS and cytokines.14
The present study represents the first attempt to determine whether SHR exhibit an altered expression (relative to WKY) of ICAM-1 on the endothelium either under baseline (constitutive) conditions or after endothelial cell stimulation with cytokines and LPS. This analysis was made possible only recently as a result of the development of a technique that allows for quantification of endothelial cell adhesion molecules with differentially radiolabeled mAbs directed against ICAM-1 or other proteins expressed on the surface of vascular endothelium (eg, ACE). Previous applications of this technique have revealed the time course and magnitude of ICAM-1 expression in different rat tissues after intraperitoneal administration of LPS21 or of E-selectin expression in porcine skin after intradermal injection of interleukin-1.39 Hence, the findings of the present study that TNF- elicits a dose-dependent increase in ICAM-1 expression in different tissues of both SHR and WKY represent novel information that should extend our understanding of the ability of this cytokine to promote the accumulation of inflammatory cells in different pathological states.
Our findings on the constitutive expression of ICAM-1 in different WKY and SHR tissues are consistent with the results of a recent study that demonstrated significant basal expression of the endothelial cell adhesion molecule in different tissues of Sprague-Dawley rats, with significant organ-to-organ variations in the constitutive level of ICAM-1 expression.21 Indeed, the magnitude of basal ICAM-1 expression that we noted in different WKY and SHR tissues is very similar to that measured in the same tissues of Sprague-Dawley rats with the same technique. Panes et al21 observed that much of the difference in ICAM-1 expression between tissues could be explained by comparable differences in endothelial cell surface area; ie, once ICAM-1 expression was normalized to endothelial cell surface area, the level of constitutive expression was similar in most tissues studied.
The results of the present study indicate that constitutive ICAM-1 expression in the microvasculature of all tissues (as well on aortic endothelium) does not differ between WKY and SHR. To correct for regional differences in endothelial cell surface area, we also normalized ICAM-1 expression to the surface expression of ACE (an endothelial cell surface marker) in the same tissues. When basal expression was normalized to the endothelial cell surface marker (ACE), the stomach and other splanchnic organs exhibited a significantly higher surface expression of ICAM-1 in SHR than WKY.
In studies of stroke-prone SHR (SHRSP) and WKY, the gene encoding for ACE has been proposed as a candidate gene in the genesis of hypertension in SHRSP.40 41 Although a higher lung ACE activity was noted in SHRSP than in WKY,42 no such difference was noted between the two groups (WKY versus SHR or SHRSP) for other tissues such as mesenteric arteries, kidney, and brain.42 43 To circumvent some of the limitations inherent in the use of anti-ACE mAbs in SHR (where surface expression of the enzyme could be affected), future studies could use mAbs directed against other endothelial cell surface proteins, such as PECAM-1.
Although few differences in ICAM-1 expression were noted between WKY and SHR under basal conditions, a blunted upregulation of ICAM-1 expression in different SHR tissues was consistently noted (relative to WKY) after endothelial cell stimulation with LPS. An increased adhesion of leukocytes to ICAM-1, intravascular coagulation, or both are unlikely explanations for the blunted responses to LPS in SHR because pretreatment with a CD11/CD18-specific mAb (CL26) and heparin did not alter the ICAM-1 upregulatory response to LPS. Furthermore, TNF- and LPS did not alter the binding of an anti-ACE mAb to endothelial cells in organs such as the heart, in which a decline in ACE expression would be expected with microcirculatory dysfunction or endothelial destruction. The blunted response of ICAM-1 upregulation was also noted in splanchnic organs of SHR receiving an intermediate dose of TNF-.
The blunted ICAM-1 upregulation observed after LPS in the brain (Figs 1d and 2) is inconsistent with published findings based on cultured endothelial cells derived from WKY and SHR brain, in which SHR-derived endothelial cell monolayers exhibited a more profound upregulation in response to LPS and cytokines.14 15 The blunted ICAM-1 upregulation in response to LPS is not likely related to alterations in responsiveness to TNF- or to the production of this cytokine. Most SHR organs that exhibited a decreased responsiveness to LPS responded to TNF-lz in a manner similar to that in WKY tissues. Furthermore, TNF- production has been shown to be increased in SHR compared with WKY.44
An explanation for the inconsistent findings between the in vitro and in vivo responses of brain endothelium to LPS is not readily available; however, it may be related to the fact that multiple cell types participate in the LPS response in vivo, which is not easily mimicked in a cell culture system. Nonetheless, our findings of an attenuated upregulation of ICAM-1 in SHR relative to WKY may explain the blunted LECA observed in mesenteric postcapillary venules exposed to acute inflammatory mediators.18 19 20 However, since the LECA elicited by platelet-activating factor and leukotriene B4 occurs so rapidly that it largely involves an interaction between CD11/CD18 on leukocytes with constitutively expressed ICAM-1 on endothelial cells, it remains unclear whether ICAM-1 upregulation is a limiting factor in the recruitment of inflammatory cells after exposure of the vasculature to such stimuli.
Recent studies45 46 have demonstrated that glucocorticoids suppress LPS- and cytokine-induced expression of adhesion molecules, including ICAM-1, on cultured endothelial cells. These observations are potentially important because higher plasma levels of glucocorticoids have been noted in hypertensive rats.47 48 Furthermore, the increased glucocorticoid level has been invoked to explain the blunted P-selectin–dependent leukocyte adhesion response elicited by histamine in SHR, since administration of a glucocorticoid receptor antagonist (RU-486) restored the histamine-induced leukocyte adhesion response to the level observed in WKY.20 To further address this possibility, we examined the influence of RU-486 on LPS-induced ICAM-1 expression. We found that RU-486 had a minimal influence on LPS-induced ICAM-1 expression, suggesting that endogenous glucocorticoids are not a major determinant of the altered ICAM-1 expression observed in SHR. These observations do not exclude the possibility that glucocorticoids may make a more significant contribution to the altered expression of other endothelial cell adhesion molecules (eg, P-selectin) in SHR.
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Acknowledgments |
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This work was supported by a grant from the National Heart, Lung, and Blood Institute, National Institutes of Health (HL-26441).
Received June 5, 1996;
first decision July 18, 1996;
first decision August 22, 1996;
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