(Hypertension. 1997;29:291.)
© 1997 American Heart Association, Inc.
Arthur C. Corcoran Memorial Lecture |
Endothelial Adhesion Molecules and Leukocyte Integrins in Preeclamptic Patients
From the Franz Volhard Clinic and the Max-Delbrück Center for Molecular Medicine, Virchow Klinikum, Humboldt University of Berlin; and the Department of Obstetrics, Neukölln Hospital (K.V.), Berlin, Germany.
Correspondence to Hermann Haller, MD, Franz Volhard Klinik, Wiltberg Strasse 50, 13122 Berlin, Germany. E-mail haller{at}mdc-berlin.de
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Endothelial cell activation is important in the pathogenesis of preeclampsia; however, the nature of the activation is unknown. We investigated 22 patients with preeclampsia, 29 normotensive pregnancies, and 18 nonpregnant women to test the hypothesis that serum from preeclamptic patients induces expression of intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1) and stimulates intracellular free calcium concentrations [Ca2+]i in cultured endothelial cells. We then asked whether the corresponding integrin adhesive counter receptors lymphocyte function-associated antigen-1 (CD11a/CD18), macrophage-1 antigen (CD11b/CD18), p150,95 (CD11c/CD18), and very late activation antigen-4 (CD49/CD29) are increased in patients with preeclampsia. In the pregnant women, the measurements were conducted both before and after delivery. Integrin expression was measured by fluorescent antibody cell sorting analysis using monoclonal antibodies. ICAM-1 and VCAM-1 were analyzed on endothelial cells by enzyme-linked immunosorbent assay. [Ca2+]i was measured with fura 2. Serum from preeclamptic patients increased endothelial cell ICAM-1 expression but not VCAM-1 expression. Preeclamptic patients' serum also increased [Ca2+]i in endothelial cells compared with serum from normal nonpregnant or normal pregnant women. Endothelial cell [Ca2+]i concentrations were correlated with the ICAM-1 expression in preeclamptic patients (r=.80, P<.001) before but not after delivery. Expression of the integrin counter receptors on leukocytes was similarly increased in preeclampsia and normal pregnancy compared with the nonpregnant state. The expression decreased significantly after delivery in both groups. Our results demonstrate that serum from preeclamptic women induces increased ICAM-1 surface expression on endothelial cells, while the expression of the integrin counterreceptors was not different. The effect on endothelial cells may be related to an increase in [Ca2+]i. The effect on cultured endothelial cells and the rapid decrease after delivery suggests the presence of a circulating serum factor which increases endothelial cell [Ca2+]i and enhances adhesion molecule expression.
Key Words: preeclampsia • adhesion molecules • VCAM • ICAM • endothelial cells • integrins • leukocytes
Abbreviations: ICAM-1 = intercellular adhesion molecule-1 • LFA-1 = lymphocyte function-associated antigen-1 • MAC-1 = macrophage-1 antigen • PE = phycoerythrin • VCAM-1 = vascular adhesion molecule-1 • VLA-4 = very late activation antigen-4
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Intact endothelial cells have antiadhesive and anticoagulant properties, regulate vascular permeability, and modulate the effect of vasoconstrictor agonists on the vessel wall.1 Several lines of evidence support the hypothesis that dysfunction of the vascular endothelium is important in the pathogenesis of preeclampsia.2–4 The vascular response to vasoconstrictors in preeclamptic women is greatly enhanced, the tendency for coagulation is increased,5–8 the capillaries are more permeable,6,9–11 and the plasma concentrations of endothelin and fibro-nectin are elevated.12–21 Glomerular capillary endothelial cells show characteristic signs of endothelial cell dysfunction.22 Indirect evidence suggests that endothelial cell leukocyte adhesion is also altered in preeclampsia; however, neither expression of endothelial cell adhesion molecules nor the leukocyte counterreceptor integrins have been investigated.
Endothelial cell leukocyte adhesion is mediated by four classes of adhesion molecules, the selectins, carbohydrate-containing selectin ligands, integrins, and immunoglobulin-like (Ig-like) molecules.23 The interaction between integrins on the surface of leukocytes and Ig-like molecules on endothelium is necessary for stable adhesion to the endothelial cells.23 The Ig-like adhesion molecules on the endothelium are ICAM-1 and VCAM-1.23 The integrins are heterodimeric glycoproteins, composed of noncovalently associated 
and ß subunits and are classified according to the structure of their ß subunits. In general, members of each class share a common ß subunit and are distinguished by their unique subunit. The four integrins that appear most important in leukocyte-endothelial adhesion are three ß2 integrins, each with a different subunit, and one ß1 integrin. The ß1 integrin is the VLA-4 integrin, also termed 4ß1 according to the integrin nomenclature, or CD49/CD29 according to the CD nomenclature. The three ß2 integrins share the ß2 chain (CD18) and are named LFA-1, also termed Lß1 or CD11a/CD18; MAC-1, also termed Mß2 or CD11b/CD18; and the glycoprotein p150,95, also termed Xß2 or CD11c/CD18.
Evidence exists for an as yet unidentified circulating factor which is released from the hypoxic placenta into the maternal circulation in preeclampsia. This factor may lead to endothelial cell activation and subsequently to endothelial cell dysfunction.2,11 Studies using serum from preeclamptic women have shown that cultured endothelial cells respond with an increased expression and release of growth factors and fibronectin, induction of oxygen radicals, as well as an inhibition of prosta-cyclin production.24–29 We tested the hypothesis that serum from preeclamptic patients induces expression of ICAM-1 and VCAM-1 on cultured endothelial cells. In addition, since signaling for such expression is known to involve cytosolic calcium [Ca2+]i,23 we tested for endothelial cell activation by measuring [Ca2+]i. We also asked whether or not the integrin adhesive counterre-ceptors LFA-1(CD11a/CD18), MAC-1(CD11b/CD18), p150,95(CD11 c/CD18) and VLA-4(CD49/CD29) were increased compared with normal pregnant and nonpregnant women.
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Patients
Fifty-one pregnant women were recruited from the Departments of Obstetrics and Gynecology of the city hospitals in Buch and Neukölln, Berlin, Germany. Twenty-two women had preeclampsia defined by hypertension, proteinuria, and hyperuricemia.30 In all cases but four, the preeclamptic patients were prima gravidae. Hypertension was defined as a blood pressure of
140/90 mm Hg systolic in the last trimester of pregnancy. Proteinuria was defined as ++ on a random urine sample or 500 mg in a 24-hour urine collection. Hyperuricemia was defined as 5.3 mg/dL. Both groups were similar in age and body weight (preeclampsia group 19 to 42 years, mean age 28 years, mean body weight 68.4±7.2 kg; pregnant control group 16 to 40 years, mean age 26 years, mean body weight 59.9±8.2 kg). Eighteen healthy, nonpregnant women (mean age 29 years) were also investigated. None of the pregnant women had a history of chronic hypertension or evidence of renal disease. All women gave signed, informed consent as determined by our committee on human subjects. Prepartum blood samples were obtained 
24 hours before delivery. Blood samples after delivery were obtained 6 to 7 days postpartum. Samples were maintained at 4°C for 4 to 6 hours before FACS analysis. For serum preparation, samples were centrifuged at 2000g for 30 minutes and stored at -20°C. For endothelial cell stimulation, the serum was diluted in medium and added to the cells in a final concentration of 2%.
Culture Procedures for Endothelial Cells
Human umbilical vein endothelial cells were isolated from umbilical cords by chymotrypsin treatment as previously described.31,32 The cords were cleaned with isotonic NaCl buffer at room temperature and were incubated for 25 minutes at 37°C with 1% chymotrypsin in PBS (Seromed). Endothelial cells were then removed by centrifugation (400g for 10 minutes). The pellet was resuspended in M-199 (Seromed) with 20% fetal calf serum, 1% L-glutamine, 1% nonessential amino acids (Seromed), 1% HEPES (GIBCO), 1% sodium pyruvate, 1% Schutz medium (Seromed), as well as with streptomycin and penicillin. Primarily cultured cells were grown for 3 to 4 days and were subcultured. Subcultures 1 and 2 were used for the experiments.
ELISA for Expression of VCAM-1 and ICAM-1 on Endothelial Cells
Experiments were carried out on 96-microtiter plates as described previously.32 The endothelial cells were seeded in the medium as described above and incubated at 37°C for 2 to 3 days. Then the medium was changed and the serum added. The medium was removed after 6 and 12 hours, respectively, and the plates were incubated with the specific antibody for VCAM-1 and ICAM-1 at a concentration of 1:1000 in Dulbecco's PBS (Seromed) with 0.2% Tween 20 (Serva) for 30 minutes at room temperature. The cells were then washed twice with PBS. Thereafter, a peroxidase-conjugate IgG antibody (goat, anti-mouse) was added (1:20.000, 30 minutes, room temperature) and followed by two washes with PBS. The color reaction was begun by adding the substrate tetramethylbenzidine dihydrochloride (Sigma). Chromophore development was determined by measuring optical density at 450 nm using a microtiter plate reader (Dynatech) and stopped by adding 2 mol/L sulfuric acid. Wells were read against blank controls containing cells incubated without the primary antibody. The reported data are derived from optical density readings well within the linear portion of the development curve (10 minutes). Values are expressed as optical density.
Measurement of [Ca2+]i in Endothelial Cells
Endothelial cells were sowed on coverslips and incubated at 37°C for 1 to 2 days. Measurements of [Ca2+]i in single cells were carried out as described previously.31 The measurements were performed using a Spex DM 3000 CM spectrofluorometer, which was connected to a Nikon epifluorescence microscope and a variable-aperture photometer for isolating individual cells on the microscope stage (Spex Industries Inc). Cultured endothelial cells were loaded with fura 2 with a 20-minute incubation in PBS containing 5 µmol/L fura 2-AM (added from a 5 mmol/L stock solution in DMSO). Fluorescence of calcium-bound and unbound fura 2 was determined by rapidly alternating (0.1 second) the exciting radiation between 340 and 380 nm and separating the resulting emission signals at 505 nm electronically. The maximal fluorescence ratio (Rmax) was determined by adding 40 µmol/L ionomycin (using a 0.01 mol/L stock solution in DMSO). The minimal fluorescence (Rmin) was obtained by adding 0.25 mol/L EGTA at pH 7.8. The ratio of the two signals was used to calculate [Ca2+]i. All experiments were carried out at room temperature. For evaluation of the different phases of the signal, [Ca2+]i was measured at the peak or highest value of the initial rise. This determination was accepted as the "peak response." After the signal had reached a stable plateau phase, the level of the "sustained response" was determined.
Immunofluorescence Analysis (FACScan) of Leukocyte Integrins
Fluorescent antibody cell sorting (FACS) analysis was carried out as described previously.32 Whole blood was collected in EDTA Vacutainers and stained with monoclonal antibodies conjugated with fluorescein (FITC) or/and PE within 6 hours after collection. Thereafter, the blood samples were treated with FACS lysing Solution (Becton Dickinson) realizing the lysis of erythrocytes and partial fixation of leukocytes. The samples were then washed two times with optimized PBS (Cellwash, Becton Dickinson), which resulted in a leukocyte suspension suitable for flow cytometry.
The cells were analyzed on a standard FACScan flow cytometer (Becton Dickinson). Flow cytometric standardization was achieved by running 6.6 mm beads (CaliBrite, Becton Dickinson) and CD-Chex (Streck Laboratories). For each sample, 10 000 cells were analyzed on the log fluorescence scale of the flow cytometer. Subsets of white blood cells were differentiated in the forward versus sideward scatter diagram and verified with specific cell markers (CD 4, CD 8 for lymphocytes, CD 14 for monocytes and CD 15 for granulocytes). The surface antigen expression, the mean log FITC, and PE-fluorescence channel of the positively stained cells were determined from a single parameter histogram.
Materials and Chemicals
For FACS analysis we employed the following antibodies and chemicals: CD4/CD8 (mouse IgG1/IgG1), CD11a (mouse IgG2a), CD18 (mouse IgG1), IgG1/IgG1 Simultest Control, mouse IgG 1 control, mouse IgG2a control, Cellwash, CaliBrite, FACS lysing solution. All products mentioned were purchased from Becton Dickinson, Immunocytometry Systems. The following antibodies were purchased from Streck Laboratories: CD11B (mouse IgG1), CD11C (mouse IgG1), CD14 (IgG2a), CD15 (IgGM), CD49d (mouse IgG1), CD29 (mouse IgG2a), mouse IgG1 control, mouse IgG2a control. The monoclonal antibodies for ICAM-1 and VCAM-1 were purchased from Biermann. The fluorescent probe fura 2-AM was purchased from Serva. All other materials, if not stated otherwise, were purchased from Sigma Chemical Co.
Statistical Analysis
Statistical analysis was carried out using a commercially available program (SPSS, SPSS Inc). The results (mean±SD) represent duplicate measurements. Normal distribution of the data was first tested by the Kolmogorov-Smirnov test. Comparisons between groups have been made by ANOVA. Comparisons of the temporal changes within groups were made by pairwise t tests with Bonferroni corrections for multiple comparisons. Differences were considered to be significant at P.05.
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In Fig 1 is shown the ICAM-1 surface expression induced by serum from preeclamptic women (n=22), normotensive pregnant women (n=29), and nonpregnant control subjects (n=18) after 12 hours. Incubation of endothelial cells with serum induced an increase in ICAM-1. Serum from preeclamptic women resulted in a significantly higher ICAM-1 expression than serum from the pregnant control group and nonpregnant women. When the incubation experiments were repeated after delivery, serum from preeclamptic women had no stimulating effect on ICAM-1 expression and was not different from the control groups (Fig 1). Interestingly, the serum from normotensive women led to a higher expression of ICAM-1 after delivery (0.24±0.021 versus 0.13±0.016, P
.05) than serum from the preeclamptic women. In contrast to the effects of serum on ICAM-1, the expression of VCAM-1 was not different between the three groups and was also not influenced by delivery (data not shown).
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We then analyzed the effects of serum from preeclamptic women on endothelial cell [Ca2+]i (Fig 2). Addition of serum led to a rapid increase in [Ca2+]i followed by a slower return to a sustained plateau slightly above basal levels. Serum from preeclamptic patients induced a significantly higher increase in peak [Ca2+]i than serum from normal pregnancy and nonpregnant control subjects. The sustained phase was not different between the three groups. The effect of serum from preeclamptic women was no longer present after delivery. We observed a positive correlation between ICAM-1 expression and [Ca2+]i in preeclamptic women (r=.80, P<.001). These data are shown in Fig 3. This correlation disappeared after delivery (r=.52, P=NS, data not shown).
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We also analyzed the expression of the integrin counterreceptors on lymphocytes, monocytes, and granulocytes, as shown in the Table and Fig 4. We observed no differences in integrin expression between preeclamptic and normal pregnant women. However, the integrin expression was higher during pregnancy in general. Both pregnant groups showed a significantly higher expression of ß1 integrin CD 18 and ß2 integrin CD 29 than non-pregnant women. The same difference was observed for the integrins CD 11a, CD 11 b, and CD 11 c, while no difference was observed for CD 49. The increased integrin expression was observed on monocytes, but not on lymphocytes. Granulocytes showed a variable pattern with an increase of CD 18, CD 11b, and CD 11 c and no difference for CD 29 and CD 11a. After delivery, the integrin expression was decreased and no longer different from non-pregnant women. The results for the ICAM-1 counterreceptor integrins LFA-1, Mac-1, and p150,95 before and after delivery are shown in Fig 3. LFA-1 expression was not different between the two groups of pregnant women, but decreased significantly after delivery in both.
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Discussion |
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We found that serum from preeclamptic women led to increased ICAM-1 expression on endothelial cells compared with serum from normal pregnant and nonpregnant women, while VCAM-1 was not influenced. Serum from women with normal pregnancy, on the other hand, showed a lower expression of ICAM-1 than did nonpregnant control subjects. Investigation of possible intracellular mediators revealed a greater response in [Ca2+]i on exposure to preeclamptic women's serum compared with control subjects. The integrin analysis on circulating leukocytes showed no significant differences between preeclampsia and normal pregnancy, but instead revealed an increased integrin expression during pregnancy in general. Our findings further support the hypothesis that endothelial cells are activated in preeclampsia.11
Other endothelial functions which have been activated in in vitro experiments involving serum from preeclamptic women are increased NO synthase and NO release,25,26 increased release of endothelin,33 and decreased release of prostacyclin.34 Furthermore, fibronectin, an important mediator of platelet aggregation, tissue factor, the most potent endogenous procoagulant activity, and von Willebrand factor, a major component of coagulation factor VIII complex, are all released from endothelial cells in vitro on stimulation with serum from preeclamptic women.27,29,35 In addition, prepartum serum from such patients has mitogenic activities,14,36 possibly due to the release of the platelet-derived growth factor PDGF.28 The stimulating effect of the serum disappears rapidly after delivery, suggesting the presence of one or more circulating endothelial activating factors in the serum of preeclamptic women. The nature of this factor(s) has not been elucidated. It has been suggested that hyperlipidemia and lipid peroxidation might contribute to this endothelium damaging effect in preeclampsia.25,26 We recently demonstrated that LDL and oxidated LDL can induce expression of endothelial adhesion molecules in vitro.32 This effect was associated with an LDL-induced increase in [Ca2+]i. However, in these experiments we observed a stimulating effect on both ICAM-1 and VCAM, rather than on ICAM-1 alone.
Our results suggest that the stimulating effect of serum from preeclamptic women on ICAM-1 may be mediated by an increase in [Ca2+]i. We and others showed earlier that [Ca2+]i was also elevated in platelets from patients with preeclampsia.30 As in the present study, the increased [Ca2+]i disappeared rapidly after delivery. A higher concentration of [Ca2+]i in endothelial cells of preeclamptic women could also be involved in the upregulation of NO synthase. We are presently investigating the hypothesis that other [Ca2+]i-dependent intracellular messengers, such as protein kinase C are involved.
The damage to endothelial cells in preeclampsia has not only been observed in vitro, but also increased circulating levels of fibronectin and von Willebrand factor have been observed in vivo. The increase in von Willebrand factor disturbed could lead to an increase in platelet activation and to alterations in the leukocyte-platelet interaction.37,38 Circulating adhesion molecules have also been investigated in preeclampsia. In contrast to our results, elevated circulating levels of VCAM-1 but not ICAM-1 were described.39,40 It is possible that VCAM-1 is more readily cleaved from the endothelial surface and thus appears in the circulation more readily than ICAM-1.
Serum from pregnant women without preeclampsia induced a lower ICAM-1 expression than both preeclamptic women and nonpregnant women. This observation suggests that in normal pregnancy, the expression of endothelial adhesion molecules is downregulated to prevent leukocyte adhesion. Since leukocyte integrins seem to be upregulated during pregnancy, a down regulation of endothelial adhesion molecules would protect from increased cell adhesion. Such a protective mechanism for cell adhesion is analogous to the increased vasorelaxant properties of the endothelium during pregnancy.3 The increased leukocyte integrin expression we observed in the third trimester of pregnancy is in agreement with earlier observations reported by Thilaganathan et al.41 Crouch et al42 on the other hand, did not observe a significant change in CD 18 and CD 11b expression during pregnancy. We did not find an effect of preeclampsia on integrin expression. Thus, increased adhesiveness of leukocytes in preeclampsia is likely due to changes on the endothelium rather than because of alterations on the leukocyte surface. Our findings appear to be the first to suggest the presence of an increased endothelial cell adhesion molecule expression in preeclampsia, suggesting that leukocyte adhesion is increased in this disease. Such increased adhesion could contribute to the enhanced coagulation and diminished fibrinolysis described by others.3,8
In summary, we observed that serum from preeclamptic women led to an increased expression of ICAM-1 on endothelial cells compared with control subjects, while VCAM-1 was not influenced. Serum from normal pregnant women, on the other hand, showed a lower expression of ICAM-1 than serum from nonpregnant control women. Investigation of possible intracellular mediators suggested a role for [Ca2+]i. An analysis of integrin counterreceptors for ICAM-1 on circulating leukocytes showed no significant differences between preeclampsia and normal pregnancy, but instead revealed an increased integrin expression during pregnancy in general. The effect of serum from preeclamptic women on cultured endothelial cells and the rapid decrease of this effect after delivery suggests the presence of a circulating endothelial cell-stimulating factor which enhances adhesion molecule expression and which may play a role in the pathogenesis of preeclampsia.
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Acknowledgment |
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This work was supported by a grant-in-aid from the Deutsche Forschungsgemeinschaft to Dr Haller (Ha 1388-7/1).
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References |
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 D. Yinon, L. Lowenstein, S. Suraya, R. Beloosesky, O. Zmora, A. Malhotra, and G. Pillar Pre-eclampsia is associated with sleep-disordered breathing and endothelial dysfunction Eur. Respir. J., February 1, 2006; 27(2): 328 - 333. [Abstract] [Full Text] [PDF]
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R. Dechend, V. Homuth, G. Wallukat, D. N. Muller, M. Krause, J. Dudenhausen, H. Haller, and F. C. Luft Agonistic Antibodies Directed at the Angiotensin II, AT1 Receptor in Preeclampsia Reproductive Sciences, February 1, 2006; 13(2): 79 - 86. [Abstract] [PDF]
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S. Zhao, Y. Zhang, Y. Gu, D. F. Lewis, and Y. Wang Heme Oxygenase-1 Mediates Up-Regulation of Adhesion Molecule Expression Induced by Peroxynitrite in Endothelial Cells Reproductive Sciences, October 1, 2004; 11(7): 465 - 471. [Abstract] [PDF]
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 J. M. Davison, V. Homuth, A. Jeyabalan, K. P. Conrad, S. A. Karumanchi, S. Quaggin, R. Dechend, and F. C. Luft New Aspects in the Pathophysiology of Preeclampsia J. Am. Soc. Nephrol., September 1, 2004; 15(9): 2440 - 2448. [Abstract] [Full Text] [PDF]
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 M. T. Elghetany and F. Lacombe Physiologic variations in granulocytic surface antigen expression: impact of age, gender, pregnancy, race, and stress J. Leukoc. Biol., February 1, 2004; 75(2): 157 - 162. [Abstract] [Full Text] [PDF]
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 T. Krauss, G. Emons, W. Kuhn, and H. G. Augustin Predictive Value of Routine Circulating Soluble Endothelial Cell Adhesion Molecule Measurements during Pregnancy Clin. Chem., September 1, 2002; 48(9): 1418 - 1425. [Abstract] [Full Text] [PDF]
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 K. Miyakoshi, H. Ishimoto, O. Nishimura, S. Tanigaki, M. Tanaka, T. Miyazaki, M. Natori, and Y. Yoshimura Role of leukocytes in uterine hypoperfusion and fetal growth retardation induced by ischemia-reperfusion Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H1215 - H1221. [Abstract] [Full Text] [PDF]
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 T. Groten, R. Kreienberg, I. Fialka, L. Huber, and D. Wedlich Altered subcellular distribution of cadherin-5 in endothelial cells caused by the serum of pre-eclamptic patients Mol. Hum. Reprod., November 1, 2000; 6(11): 1027 - 1032. [Abstract] [Full Text] [PDF]
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J. GREEN, S. ASSADY, F. NAKHOUL, T. BICK, P. JAKOBI, and Z. ABASSI Differential Effects of Sera from Normotensive and Hypertensive Pregnant Women on Ca2+ Metabolism in Normal Vasular Smooth Muscle Cells J. Am. Soc. Nephrol., July 1, 2000; 11(7): 1188 - 1198. [Abstract] [Full Text]
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 R. Dechend, V. Homuth, G. Wallukat, J. Kreuzer, J. K. Park, J. Theuer, A. Juepner, D. C. Gulba, N. Mackman, H. Haller, et al. AT1 Receptor Agonistic Antibodies From Preeclamptic Patients Cause Vascular Cells to Express Tissue Factor Circulation, May 23, 2000; 101(20): 2382 - 2387. [Abstract] [Full Text] [PDF]
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