Leukocyte behaviour and permeability in the rat mesenteric microcirculation following induction of ovulation

Tomihiro Katayama1, Yasuki Kusanagi, Masaki Kiyomura, Hiroshi Ochi and Masaharu Ito

Department of Obstetrics and Gynecology, Ehime University School of Medicine, Shitsukawa, Shigenobu, Ehime 791-0295, Japan

1 To whom correspondence should be addressed. e-mail: tkatayam{at}m.ehime-u.ac.jp


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
BACKGROUND: Ovarian hyperstimulation syndrome (OHSS), a highly dangerous and incompletely understood complication of ovulation induction with exogenous gonadotrophins, can include haemoconcentration, hypovolaemia, hypotension, acute renal insufficiency, thromboembolism and ultimately death. Using intravital microscopy, we examined microvascular permeability and leukocyte–endothelial cell interactions in the rat mesenteric microcirculation associated with induction of ovulation. METHODS: In female rats treated with hMG and hCG, mesenteric venules were observed by intravital microscopy assisted by a video imager. Erythrocyte velocity was monitored, and rolling and adhesion of leukocytes were studied by transmission video images. Transvascular leakage of fluorescein isothiocyanate-labelled albumin was assessed by epi-illumination. RESULTS: Administration of hMG and hCG significantly increased vascular protein leakage within a few hours, and also reduced rolling velocities of leukocytes in venules and increased numbers of leukocytes adherent to endothelium at 16 h following hCG injection. The administration of antibodies against intracellular adhesion molecule (ICAM)-1 inhibited these reactions. CONCLUSION: By induction of ovulation, vascular permeability is increased not only at the surface of the ovary but also in the mesentery. Alteration of leukocyte behaviour in the microcirculation through mechanisms involving ICAM-1 is one likely cause of the protein leakage.

Key words: endothelial permeability/intracellular adhesion molecule (ICAM)-1/leukocyte behaviour/microcirculation/ovarian hyperstimulation syndrome (OHSS)


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Ovarian hyperstimulation syndrome (OHSS) is a constellation of clinical events representing the most serious complication resulting from use of gonadotrophins for ovulation induction (Schenker and Weinstein, 1978Go). OHSS occurs in a life-threatening form in 0.5–2% of assisted reproduction treatment cycles, amounting to at least 50 000 affected cycles in 1995 (Forman et al., 1990Go). OHSS is characterized by two major components: sudden bilateral ovarian enlargement and an acute shift of intravascular fluid into the third space. Clinical manifestations of severe OHSS in addition to ovarian enlargement include ascites, pleural effusion, electrolyte abnormalities, hypovolaemia, oliguria, haemoconcentration, hyper coagulability and liver dysfunction. Exceptionally, respiratory distress syndrome, hypovolaemic shock, renal failure and even death may ensue (Schenker, 1993Go). The pathogenesis of this state is not completely understood, and no specific therapy or prevention is available.

Certain inflammatory cytokines (interleukin-6, tumour necrosis factor-{alpha} and interleukin-1) and growth factors such as vascular endothelial growth factor may play major roles in the pathophysiology of systemic acute-phase responses (Sirois and Edelman, 1997Go; Tamion et al., 1997Go). On the other hand, a rapidly expanding body of data has highlighted the importance of endothelial cell adhesion molecules in development and propagation of inflammatory processes in many human tissues (Simmons et al., 1988Go; Springer et al., 1990Go; Bevilacqua et al., 1993Go; Carlos et al., 1994Go). These molecules facilitate leukocyte adhesion and extravasation through the vessel wall, which are key steps in response to infection and tissue injury. Adhesion molecules such as vascular cell adhesion molecule-1 and intracellular adhesion molecule (ICAM)-1, are transmembrane glycoproteins that are members of the immunoglobulin superfamily (Aoki et al., 1997Go; Iigo et al., 1997Go; Morisaki et al., 1997Go). This group of molecules includes major mediators of white blood cell adhesion, interaction and extravasation during inflammatory and immune reactions. Recent reports indicate that amounts of ICAM-1 in the blood correlate with biological and clinical aspects of severe OHSS (Daniel et al., 1999Go; Abramov et al., 2001Go; Bonello et al., 2002Go). OHSS may be seen as a disorder where adhesion molecules are involved in exaggerated leukocyte recruitment and transendothelial migration, causing tissue damage and capillary hyperpermeability.

Although occurrence of increased vascular permeability is not limited to ovulation, OHSS can be viewed as an exaggeration of events that occur during the menstrual cycle (Cavender et al., 1988Go). Investigation of changes in microvascular permeability at ovulation, therefore, is important to understanding the cause of OHSS. Until now, little has been known about sequential multistep leukocyte–endothelium interactions and albumin leakage from endothelial cells in the microcirculation at induction of ovulation.

We therefore used intravital microscopy to examine the microvascular permeability and behaviour of leukocytes involving adhesion molecules in the rat mesenteric microcirculation accompanying induction of ovulation (Suematsu et al., 1995Go; Katayama et al., 2000Go).


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Animals
Experimental procedures were approved by the Animal Care and Utilization Committee of Ehime University School of Medicine. Female 11-week-old Wistar rats were purchased from CLEA Japan (Tokyo). Rats were maintained under standard pathogen-free conditions, and experiments were performed at 12 weeks of age.

Intravital observation of neutrophil adhesion and FITC-labelled albumin leakage in rat mesenteric venules
After rats were anaesthetized with pentobarbital sodium (40 mg/kg, i.m.), the femoral vein was cannulated with a polyethylene catheter (Atom, Tokyo, Japan) for infusion of monoclonal antibody (mAb) and fluorescein isothiocyanate-labelled bovine serum albumin (FITC– BSA). The abdomen was opened via a midline incision, and the ileocaecal portion of the mesentery was gently exposed and mounted on a plastic stage. Postcapillary venules 20–40 µm in diameter were selected for evaluation of leukocyte adhesion as described previously (Suematsu et al., 1989Go), and were visualized with an intravital microscope (BX50: Olympus, Tokyo, Japan) assisted by a high-resolution colour charge-coupled device (CCD) camera (HCC-600: FLOVEL, Tokyo, Japan). The mesentery was superfused continuously with Krebs–Henseleit bicarbonate-buffered solution saturated with 95% N2/5% CO2 at 37°C. Centreline erythrocyte velocity (VR) in selected venules was monitored continuously by a temporal correlation velocimeter (Instrumentation for Physiology and Medicine, San Diego, CA). To minimize effects of surgical insults on observed leukocyte adhesion, the preparation was allowed to stabilize for 30 min after abdominal surgery. Leukocyte behaviour in venules was videotaped continuously by an S-VHS video recorder (RS-232C: Panasonic, Tokyo, Japan). The density of adherent leukocytes was expressed as their number per 100 µm segment of venule. Adherent leukocytes were defined as those remaining stationary for >30 s in the same portion of the selected venular segment. Rolling leukocytes were defined as those moving at a velocity less than that of erythrocytes in the same vessel. White blood cell velocity, VW, was determined as the time required for a leukocyte to transverse a given length of venule, as described previously (Morisaki et al., 2001Go, 2002). Venular wall shear rates ({gamma}) were calculated according to the formula {gamma} = 5(VR/DV), with DV representing venular diameter, as described elsewhere (House et al., 1987Go).

Vascular albumin leakage was quantified using a previously reported protocol (Kubes et al., 1996Go). Briefly, FITC–BSA (25 mg/kg: Sigma Chemical, St Louis, MO) was administered i.v. to animals 15 min before the start of the experimental procedure. Fluorescence intensity (excitation wavelength, 420–490 nm; emission wavelength, 520 nm) was detected using a silicon-intensified fluorescence camera (model C2400-08: Hamamatsu Photonics, Hamamatsu, Japan). Images were recorded for playback analysis using a videocassette recorder (Figure 1). The fluorescent intensity representing FITC–BSA was measured within a defined area (10 x 30 µm) of the venule under study as well as in the adjacent perivascular interstitium. An index of vascular albumin leakage (DPE/DCE) was determined as a ratio using the formula [(interstitial intensity – background intensity)/(venular intensity – background intensity)] x 100 (maximal value, 100), as previously described.



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Figure 1. Apparatus for in-vivo visualization of endothelial permeability and leukocyte behaviour in rat mesenteric microvascular beds.

 
Experimental protocols
Eight main protocols were employed for intravital observation of neutrophil adhesion and permeability of the rat mesenteric microcirculation to injected FITC–BSA. Rats in the first group were examined in the estrus phase, characterized by cornified cells in the vaginal smear, after monitoring the animals for several days before to decide the cycle stage. In the second group, rats were observed in the post-estrus phase, which shows pavement cells and leukocytes in the vaginal smear. Animals in the third group received an i.p. injection of 50 IU of hMG (Nikken: Denka Phamaceutical, Kanagawa, Japan) in the diestrus phase, which shows epithelial cells and leukocytes in the vaginal smear. Observations were made at 70 h after hMG. In groups 4–7, hMG was followed 54 h later by 50 IU i.p. of hCG (Mochida Phamaceutical, Tokyo, Japan). Observations were made 4, 8, 12 or 16 h after hCG. Rats in the eighth group received hMG and hCG as in groups 4–7, but also underwent i.v. injection of mAbs against ICAM-1 (murine immunoglobulin G1 anti-ICAM-1 monoclonal antibody; 1A29, 1 mg/kg, CHEMICON, CA) 8 h after the hCG injection (Morisaki et al., 1997Go); observations were made 8 h later.

Systemic haematocrit measurement
Three small samples of blood obtained from the carotid artery were placed in heparinized capillary tubes (Hemato-Clad Heparinized, Drummond Scientific Company, Broomall, PA), which were spun in a centrifuge (Bilmeter-E, Mochida Phamaceutical, Tokyo, Japan) for 3 min at 7000 g to separate the total blood volume into red blood cell and plasma in order to calculate the haematocrit (Hct).

Statistical analysis
Differences of the data among groups were examined by one-way ANOVA with Fisher’s multiple comparison test. P-values <0.05 were considered to be significant throughout the current study.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Success rate for ovulation and changes of Hct accompanying i.p. injection of HMG and HCG
I.p. injection of 50 IU of hMG was followed 54 h later by 50 IU of hCG. The success rate of ovulation was 100% at 16 h after the injection of hCG (n = 5). No significant change in Hct occurred with induction of ovulation.

Changes of erythrocyte velocity, vessel diameter and shear rate
Table I shows the shear rate for post-capillary venules in the estrus phase, in the metestrus phase and in the gonadotrophin-treated groups. VR and DV in the microcirculation of the injected groups did not differ significantly. Shear rates in arterioles and venules also did not differ among these groups. The absence of differences among the seven groups in behaviour of erythrocytes permitted consideration of the velocity and density of leukocytes as an index of leukocyte– endothelium adhesive interactions.


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Table I. Shear rate in mesenteric venules in each group (n = 5 per group)
 
Altered microvascular permeability
Figure 2A–C shows representative images of microvascular behaviour of exogeneous injected FITC–BSA in vivo, with arrows in these images indicating blood flow. An index of venular permeability was measured on-line as the degree of leakage of FITC–BSA from the venules into the interstitium. Figure 2A is a microfluorograph captured at 30 frames/s in the estrus phase, with the interstitium around the venules showing very little fluorescence (i.e. negligible leakage of FITC–BSA). Figure 2B is representative of the metestrus phase, in which the interstitium surrounding the venules shows relatively low intensity of FITC–BSA fluorescence, but nonetheless more than in the estrus group, which indicates very mild albumin leakage in the metestrus phase. Figure 2C is representative of the group receiving 50 IU of vhMG by i.p. injection followed 54 h later by 50 IU of hCG, at 16 h after hCG injection. Leakage of FITC–BSA shows much higher fluorescence intensity than in the estrus group or the metestrus group. When ovulation was induced by exogenous hMG and hCG, leakage of albumin occurred from mesenteric microvessels as well as presumably on the surfaces of ovaries. Figure 2D shows the spatial and temporal transition of the microvascular permeability related to injection of hMG and hCG. No significant increase in permeability resulted from treatment with only HMG. DPE/DCE rose in a time-dependent manner after hCG was administered. The DPE/DCE 8 h after hCG was significantly greater than in the estrus group (P < 0.05). DPE/DCE also increased from that time.



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Figure 2. Representative microfluorographs captured at 30 frames/s, showing the distribution of exogeneously injected FITC–BSA in vivo. (A) Estrus phase. Arrows denote the direction of blood flow. Bar = 40 µm. (B) Metestrus phase. (C) The effect of i.p. injection of 50 IU of hMG followed 54 h later by 50 IU of hCG. The microfluorograph was taken 16 h after hCG injection. (D) Spatial and temporal transition of microvascular permeability associated with injection of hMG and hCG. Values indicate means ± SD from five different rats in all groups. *P < 0.05 compared with the estrus group.

 
Interaction between leukocytes and endothelium on induction of ovulation
Figure 3A is a histogram of the leukocyte rolling velocity normalized to erythrocyte velocity (VW/VR) in estrus, metestrus and treated groups. VW/VR histograms could be closely approximated by a distribution with a median value of 2–3% of VR in estrus and metestrus groups, which did not differ in distribution or median value (Figure 3B). In the hMG 70, hMG 54 – hMG 4 and hMG 54 – hCG 8 groups, distributions of the normalized leukocyte rolling velocity were not altered from those in the estrus or metestrus groups. In the hMG 54 – hCG 12 group, increased numbers of animals showed a VW/VR below 2%. In the hMG 54 – hCG 16 group, the relative leukocyte rolling velocity was decreased significantly. Numbers of adherent leukocytes in postcapillary venules are presented in Table II. The number of adherent leukocytes in the hMG 54 – hCG 16 group was significantly greater than in the control groups. The interaction between leukocytes and endothelium was greatest in the hMG 54 – hCG 16 group.



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Figure 3. Leukocyte behaviour. (A) Histogram of the leukocyte rolling velocity in estrus, metestrus, hMG 70, hMG 54 – hCG 4, hMG 54 – hCG 8, hMG 54 – hCG 12 and MG 54 – hCG 16 groups of female Wistar rats. Numbers in the group designations refer to the intervening hours. VW/VR (%) denotes the ratio between rolling velocity of marginating leukocytes in rat mesentery postcapillary venules and centreline erythrocyte velocity, as a measure of membrane adhesion between neutrophils and endothelium. Each histogram was prepared from 500 measurements of rolling velocity in five animals for each group. (B) Effects of hMG and hCG on the leukocyte–endothelial cell interactions in venules. The calculations were based on five means for each group. *P < 0.05 compared with the estrus group.

 

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Table II. Adherent leukocyte number in postcapillary venules in each group (n = 5 per group)
 
Relationship between leukocyte adhesion and permeability in the microcirculation during induction of ovulation
We determined the effects of an mAb against ICAM-1 in our in-vivo systems. Figure 4 shows alterations in microvascular permeability (DPE/DCE) and behaviour of leukocytes (VW/VR) induced by the induction of ovulation, and also depicts effects of the monoclonal anti-ICAM-1 on these parameters. The reduction of the leukocyte rolling velocity and increased numbers of adherent leukocytes were noted with induction of ovulation, denoting increasing adhesiveness between leukocytes and endothelial cells. Alteration of permeability by induction of ovulation was apparent concurrent with the interaction between leukocytes and endothelial cells. Pretreatment with mAb 1A29 significantly attenuated both the increase in microvascular permeability and the adhesion of leukocytes associated with injection of hMG and hCG.



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Figure 4. Effects of mAb (1A29) against ICAM-1 on the changes associated with induced ovulation in permeability (DPE/DCE) and leukocyte behaviour (VW/VR, adherent cells). The calculations were based on five means for each group. *P < 0.05 versus the hMG 54 – hCG 16 group.

 

    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
OHSS is a dramatic complication of gonadotrophin treatment. Its most severe forms can be fatal, or include haemoconcentration, hypovolaemia, hypotension, acute renal insufficiency and thromboembolism. Although many reports have been published about the pathophysiology of this syndrome, its exact mechanisms still are not fully elucidated. In the present study using intravital microscopy, we examined microvascular permeability and leukocyte–endothelium interaction in rat mesenteric microcirculation during induction of ovulation.

Administration of hMG followed by hCG significantly increased vascular protein leakage within a few hours of the latter injection. After 16 h, rolling velocities of leukocytes in venules were reduced and numbers of leukocytes adherent to endothelium were increased. The results of the present study demonstrate alterations of permeability and interactions between leukocytes and endothelial cells in mesenteric postcapillary venules associated with induction of ovulation. Permeability of mesenteric venules gradually increased after injection of hCG, and leukocyte adhesion rose concurrently.

With regard to increased permeability associated with leukocyte adhesion, most in-vitro and in-vivo studies have demonstrated that leukocyte adhesion, leukocyte emigration and increased protein leakage are closely related. Studies in cat mesentery demonstrated that both platelet-activating factor (PAF) and leukotriene B4 (LTB4) promoted leukocyte adherence in postcapillary venules, but only PAF-induced leukocyte adherence increased vascular protein leakage (Kubes et al., 1991Go). These investigators proposed that differences in induced oxidant production between these two inflammatory mediators might be related to these distinctive permeability responses. Thus, attachment of leukocytes to the endothelial cells lining the walls of small vessels may not always result in increased microvascular permeability. However, leukocyte adhesion in frog mesentery venules induced by low flow rate was associated with a sustained significant increase in permeability, which differed from the transient increase in permeability that another investigator observed when the venule was exposed to inflammatory mediators (He and Curry, 1994Go; He et al., 1996Go). A previously reported in-vivo method was used successfully to study leukocyte adhesion and its effect on permeability of the microvasculature. Leukocyte adhesion induced by low flow rate caused a sustained increase in hydraulic conductivity in the venules of frog mesentery. In that system, increasing intracellular cAMP prevented the permeability increase associated with leukocyte adhesion without affecting the adhesion process (He et al., 2000Go). These observations indicated that cAMP-dependent mechanisms regulate increases in permeability from inflammatory agents that do not necessarily affect leukocyte adhesion to the venular wall. Thus, interaction between leukocytes and endothelial cells is one of multiple possible causes of increased permeability. In our hMG 54 – hCG 16 group, leukocyte rolling velocity and leukocyte adhesion, which are indices of interactions between leukocytes and endothelial cells, were altered significantly. At this time point, microvascular permeability most probably was increased as a result of leukocyte adhesion.

The mechanism underlying the clinical manifestations of OHSS appears to be an increase in capillary permeability of the ovarian vessels and those of other mesothelial surfaces (Mordel et al., 1993Go; Schenker et al., 1993Go; Goldsman et al., 1995Go). In this study, we did not examine ovarian albumin leakage, but instead visualized mesenteric postcapillary venules at induction of ovulation. Lowered peripheral vascular resistance, tachycardia and increased cardiac output were observed in 31 consecutive cases of severe OHSS; whether vasodilation preceded or followed any increase in capillary permeability in these patients, or whether the two in fact were related, was unclear (Mathur et al., 1997Go). Arteriolar dilation is probably not the sole cause of increased transudation of fluid into the extravascular space at ovulation, since no arteriolar dilation occurred upon induction in our present study.

Soluble forms of the adhesion molecule ICAM-1 assayed in serum have been reported to correlate with biological and clinical features of severe OHSS (Abramov et al., 2001Go). These endothelium–leukocyte adhesion molecules therefore may be involved in the pathophysiology of the syndrome. Leukocyte-mediated tissue damage is a major component of various human disease processes, including adult respiratory distress syndrome, autoimmune disease, graft rejection and ischaemia– reperfusion injury. Endothelial cell–leukocyte adhesion molecules have been implicated as mediators in most of these disorders. OHSS may be another entity where adhesion molecules exaggerate leukocyte recruitment and transendothelial leukocyte migration, causing tissue damage and capillary hyperpermeability. ICAM-1 is a member of the immunoglobulin superfamily that is also expressed by vascular endothelial cells. It contains five extracellular immunoglobulin domains that can bind to leukocytes through specific integrins on their surface, mostly {beta}2-integrins. ICAM-1 is expressed in abundance on vascular endothelium after several hours of stimulation by inflammatory cytokines. While endothelial cell surface ICAM-1 appears to contribute to adhesion and transmigration of most leukocyte types through interaction with {beta}2-integrins, neutrophils, monocytes, lymphocytes and natural killer cells all express CD11a/18, which also has been shown to bind to ICAM-1 (Springer et al., 1990Go). In the present study, pretreatment with mAb against ICAM-1 significantly inhibited the increase of microvascular permeability and adhesion of leukocytes associated with injection of hMG and hCG. OHSS may be one of several disease entities in which these adhesion molecules cause harmful leukocyte recruitment.

Albumin leakage, but not leukocyte adhesion, was evident at 8 h after injection of hCG, while leukocyte rolling velocity was significantly decreased at 16 h after injection of hCG. Mediators such as histamine, bradykinin and serotonin induce a leukocyte-independent increase in microvascular permeability, while actions of PAF, cytokine-induced neutrophil chemoattractant/growth-related oncogene (CINC/gro), LTB4, formyl-Meth-Leu-Phe (fMLP) as well as more complex models of inflammation such as ischaemia–reperfusion injury show a neutrophil-dependent component (Wedmore et al., 1981Go; Kubes et al., 1996Go). Histamine-induced albumin leakage occurs rapidly prior to any changes in leukocyte adhesion. Histamine or other leukocyte-independent mediators may be involved in the early hyperpermeability observed at 8 h after injection of hCG.

Levin et al. (1995Go) described 22 patients with severe OHSS, five of whom had pleural effusion (23%). Notably, however, capillary accumulation of stimulated leukocytes at physiological shear rates appears to be unique to the pulmonary microcirculation. In other organs such as heart, brain and skeletal muscle, leukocyte entrapment in capillaries occurs only when the microvascular system is exposed to low-shear conditions elicited by haemorrhagic shock or ischaemia. This difference is reflected in observed intravascular events. First, leukocyte rolling, a caterpillar-like movement, is not observed in unstimulated leukocytes within arterioles or venules in the lungs, while the same leukocytes roll and adhere to venules in other organs. This finding indicates that under experimental conditions, transient interactions between leukocytes and endothelium in steady-state lung are quite different from those in other organs. Secondly, blockade of SLeX, a ligand for P-, E- and L-selectins, does not alter the leukocyte behaviour in the lung. Thirdly, when activated, leukocytes were trapped mainly in the pulmonary microvasculature despite the absence of L-selectin (Aoki et al., 1997Go). One cause of pleural effusion in OHSS appears to be an interaction between leukocytes and pulmonary vascular endothelium.

In conclusion, our study demonstrated that albumin leakage from mesenteric venules occurs on induction of ovulation by administration of hMG and hCG. Further, albumin leakage is followed by interactions between leukocytes and endothelial cells. Pretreatment with mAb against ICAM-1 significantly inhibited the increase in microvascular permeability and adhesion of leukocytes. ICAM-1 may be important in these leukocyte behaviours and changes in permeability, which are likely to be similar in OHSS.


    Acknowledgement
 
This study is supported by Grant-in-Aid No.14770855 for Scientific Research from the Ministry of Education, Science and Culture of Japan.


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 Discussion
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Submitted on December 9, 2002; accepted on February 25, 2003.