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Hypertension. 1995;26:401-405

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(Hypertension. 1995;26:401-405.)
© 1995 American Heart Association, Inc.

Articles

Inhibition by Cardiac Natriuretic Peptides of Rat Vascular Endothelial Cell Migration

Miwako Ikeda; Masakazu Kohno; Tadanao Takeda

From the First Department of Internal Medicine, Osaka City (Japan) University Medical School.

Correspondence to Miwako Ikeda, MD, Division of Hypertension and Atherosclerosis, First Department of Internal Medicine, Osaka City University Medical School, 1-5-7 Asahi-machi, Abeno-ku, Osaka 545, Japan.


*    Abstract
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 *Abstract
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Abstract Vascular endothelial cell migration is proposed to be an important process in the initiation and progression of atherosclerosis. We designed the present study to examine the effects of atrial and brain natriuretic peptides on fetal calf serum–stimulated migration of cultured rat aortic endothelial cells using Boyden's chamber method. Fetal calf serum clearly stimulated migration in a concentration- and time-dependent manner. Rat atrial natriuretic peptide-(1-28) and rat brain natriuretic peptide-45, which are the major circulating forms of atrial and brain natriuretic peptides in rats, inhibited fetal calf serum–stimulated migration in a concentration-dependent manner between 10-10 and 10-6 mol/L. Such inhibition by these natriuretic peptides was paralleled by an increase in the cellular level of cGMP. The addition of a cGMP analogue 8-bromo-cGMP, significantly inhibited fetal calf serum–stimulated migration in a concentration-dependent manner between 10-7 and 10-3 mol/L. Rat atrial natriuretic peptide-(5-25) was much less effective than atrial natriuretic peptide-(1-28) or rat brain natriuretic peptide-45 with respect to inhibiting migration and increasing cGMP levels. These results indicate that atrial and brain natriuretic peptides inhibit fetal calf serum–stimulated vascular endothelial cell migration, probably through a cGMP-dependent process.


Key Words: natriuretic peptides • vascular endothelium • cell movement • rats


*    Introduction
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 *Introduction
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The migratory activity of vascular endothelial cells is proposed to play an important role in the initiation and progression of atherosclerosis. A number of agents, including serum,1 2 acidic,3 and basic fibroblast growth factors,4 and high-density lipoprotein5 stimulate endothelial cell movement in vitro.

ANP was originally isolated from mammalian hearts.6 A second type of natriuretic peptide has been identified in the porcine brain.7 Designated as BNP, it has subsequently also been isolated from mammalian heart.8 9 It has been demonstrated that ANP and BNP exert an antiproliferative effect on bovine aortic endothelial cells via a guanylate cyclase–coupled mechanism.10 However, the roles of the natriuretic peptides on vascular endothelial cell migration remain to be elucidated despite the existence of a large number of gyanylate cyclase–coupled natriuretic peptide receptors in these cells.11 12 13

Accordingly, we designed the present study to examine the possible effects of rat ANP-(1-28) and rat BNP-45, which are the major circulating forms of ANP and BNP in rats,14 15 on rat vascular endothelial cell migration after stimulation with FCS. In addition, the effect of rat ANP-(5-25), which is much weaker biologically than rat ANP-(1-28) or rat BNP-45, on migration was also examined in these cells.


*    Methods
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 *Methods
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Materials
DMEM, FCS, trypsin, Versine, penicillin, and streptomycin were purchased from GIBCO Laboratories. Synthetic rat ANP-(1-28) and rat BNP-45 were purchased from Peptide Institute, Inc. Rat ANP-(5-25) was purchased from Peninsula Laboratories, Inc. 8-Bromo-cGMP, IBMX, and endothelial cell growth supplement were purchased from Sigma Chemical Co. cGMP assay kit was purchased from Yamasa Shoyu Co.

Endothelial Cell Culture
Vascular endothelial cells were grown from the explants of the thoracic aorta of male Wistar rats weighing 50 to 100 g as previously described.16 Briefly, small segments of aortic tissue were placed endothelial-side down on the surface of culture dishes and maintained in DMEM containing 7% FCS, endothelial cell growth supplement (50 µg/mL), penicillin (50 µg/mL), and streptomycin (50 µg/mL) with atmospheric air and 5% CO2. The cells that migrated from the explants were removed by trypsinization and seeded in culture flasks. Endothelial cells were identified by their "cobblestone" appearance by phase-contrast microscopy and positive fluorescence with factor VIII antigen and negative fluorescence with antibodies against {alpha}-smooth muscle actin. Contamination by cells with the morphological features of smooth muscle cells was not found. Cells after two to five passages were used for the experiment.

Migration Assay
Endothelial cell migration was assayed by a modification of Boyden's chamber method with the use of a microchemotaxis chamber (Neuro Probe, Inc) and polycarbonate filters (Nucrepore Corp) with pores 5.0 µm in diameter, as previously reported by Koyama et al.17 Cultured endothelial cells were trypsinized and suspended with a concentration of 5.0x105 cells per milliliter in DMEM supplemented with 0.5% bovine serum albumin. The cell number was counted with an electronic cell counter (model ZB1, Coulter Electronica). A 200-µL volume of cell suspension was placed in the upper chamber, and 35 µL of DMEM containing 5% FCS with or without various concentrations of rat ANP-(1-28), rat BNP-45, rat ANP-(5-25) (10-12 to 10-6 mol/L), or 8-bromo-cGMP (10-7 to 10-3 mol/L) was placed in the lower chamber. The chamber was incubated at 37°C with atmospheric air and 5% CO2 for 4 hours. The cells on the upper side of the filter were scraped off, and the filter was removed. Cells that had migrated to the lower side of the filter were fixed in ethanol, stained with Diff-Quick staining solution (The Green Cross Corp), and counted under a microscope (magnification x400) for quantitation of endothelial cell migration. Migratory activity is expressed as the sum of the number of cells that were observed in four high-power fields.

cGMP Measurement
After preincubation the cell monolayers were washed twice with phosphate-buffered saline and then stimulated for 30 minutes with different concentrations of rat ANP-(1-28), rat BNP-45, or rat ANP-(5-25) dissolved in DMEM that contained 5% FCS and 0.5 mmol/L IBMX. The reaction was stopped by rapid aspiration and the addition of 2 mL ice-cold 65% ethanol. After evaporation by a centrifuge evaporator, the dry residue was dissolved in an assay buffer. cGMP levels were determined by radioimmunoassay done with a cGMP assay kit as previously described.12 13

Calculations and Statistical Analysis
The statistical significance of differences in the studies was evaluated by ANOVA, and P values were calculated by Scheffé's method.18 Values are expressed as mean±SD.


*    Results
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 *Results
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Effect of FCS on Endothelial Cell Migration
Fig 1 shows the effects of various concentrations (1%, 3%, 5%, 10%, and 20%) of FCS on endothelial cell migration. FCS stimulated cell migration in a concentration-dependent manner. Endothelial cell migration increased during the initial 4 hours of incubation, after which the rate of increase declined significantly. Therefore, subsequent studies on endothelial cell migration were done with cells incubated for 4 hours. Nonstimulated endothelial cells did not exhibit any migratory activity even after 8 hours.



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  		Figure 1. Line graph shows time-dependent effects of various concentrations of FCS on endothelial cell migration. Migratory activities were assayed in quadruplicate; values are expressed as mean±SD for the number of cells observed in four high-power fields (HPF). {circ} indicates without FCS; {bullet}, 1% FCS; {square}, 3% FCS; {triangleup}, 5% FCS; {blacksquare}, 10% FCS; and {blacktriangleup}, 20% FCS.

Effects of Natriuretic Peptides on Endothelial Cell Migration
Effects of various concentrations (10-6, 10-8, 10-10, and 10-12 mol/L) of rat ANP-(1-28), rat BNP-45, and rat ANP-(5-25) on endothelial cell migration after stimulation with 5% FCS are shown in Fig 2. Rat ANP-(1-28) significantly inhibited migration at concentrations of 10-8 and 10-6 mol/L and tended to inhibit migration at a concentration of 10-10 mol/L. Rat BNP-45 significantly inhibited migration at concentrations between 10-10 and 10-6 mol/L. In parallel with the inhibition by rat ANP-(1-28) and rat BNP-45 on FCS-stimulated migration, cellular cGMP increased after treatment with rat ANP-(1-28) and rat BNP-45 (Fig 3). There was a significant inverse correlation between the increase in cellular cGMP levels and the decrease in migratory activity by ANP and BNP (n=12, r=.76, P<.01) (Fig 4).



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  		Figure 2. Line graph shows effects of various concentrations of rat ANP-(1-28) ({bullet} with solid line), rat BNP-45 ({square}), and rat ANP-(5-25) ({bullet} with dotted line) on migration of endothelial cells stimulated by 5% FCS. Migratory activities were assayed in quadruplicate; values are expressed as mean±SD for the number of cells observed in four high-power fields (HPF). *P<.05 vs 5% FCS alone.



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  		Figure 3. Line graph shows effects of various concentrations of rat ANP-(1-28) ({bullet} with solid line), rat BNP-45 ({square}), and rat ANP-(5-25) ({bullet} with dotted line) on cellular cGMP level in cultured endothelial cells treated with 5% FCS. Values are expressed as mean±SD of four measurements. *P<.05 vs 5% FCS alone.



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  		Figure 4. Scatterplot shows correlation between percent increase in cellular cGMP level and percent decrease in migratory activity of endothelial cells treated with various concentrations of rat ANP-(1-28), rat BNP-45, or rat ANP-(5-25) in the presence of 5% FCS.

Rat ANP-(5-25) was much less effective than rat ANP-(1-28) or rat BNP-45 with respect to inhibiting migration and increasing cGMP levels (Figs 2 and 3). Rat ANP-(5-25) significantly inhibited migration only at the highest concentration (10-6 mol/L).

To confirm the inhibitory effect of natriuretic peptides on endothelial cell migration, we examined the effects of 10-6 mol/L rat ANP-(1-28), rat BNP-45, and rat ANP-(5-25) on endothelial cell migration stimulated by various concentrations of FCS (5%, 10%, and 20%) (Fig 5). Both rat ANP-(1-28) and rat BNP-45 at a concentration of 10-6 mol/L significantly inhibited migration stimulated by 5% to 20% FCS. Rat ANP-(5-25) at 10-6 mol/L also inhibited migration stimulated by 5% to 20% FCS, but this inhibition was significantly weaker than that of rat ANP-(1-28) or BNP-45.



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  		Figure 5. Line graph shows effects of 10-6 mol/L rat ANP-(1-28) ({bullet} with solid line), rat BNP-45 ({square}), and rat ANP-(5-25) ({bullet} with dotted line) on the migration of endothelial cells stimulated by various concentrations (5%, 10%, and 20%) of FCS. Migratory activities were assayed in quadruplicate; values are expressed as mean±SD for the number of cells observed in four high-power fields (HPF). *P<.05 vs FCS alone ({circ}).

Effect of 8-Bromo-cGMP on Endothelial Cell Migration
To determine whether the inhibitory effects of natriuretic peptides on endothelial cell migration after stimulation with FCS are causally linked to the increase in cellular cGMP, we examined the effect of a cGMP analogue, 8-bromo-cGMP, on 5% FCS–stimulated endothelial cell migration (Fig 6). 8-Bromo-cGMP inhibited FCS-stimulated migration in a concentration-dependent manner between 10-7 and 10-3 mol/L.



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  		Figure 6. Line graph shows effects of various concentrations of 8-bromo-cGMP on the migration of endothelial cells stimulated by 5% FCS. Migratory activities were assayed in quadruplicate; values are expressed as mean±SD for the number of cells observed in four high-power fields (HPF). *P<.05 vs 5% FCS alone.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
We have confirmed previous reports1 2 using Boyden's chamber method that FCS potently stimulates vascular endothelial cell migration in a concentration- and time-dependent manner, although we have not elucidated its mechanism.

We also showed that rat ANP-(1-28) and rat BNP-45, which are the major circulating forms of ANP and BNP in rats,14 15 inhibit the migration of cultured rat vascular endothelial cells after stimulation with FCS in a concentration-dependent manner between 10-10 and 10-6 mol/L. To our knowledge this is the first demonstration concerning the relationship of cardiac natriuretic peptides and vascular endothelial cell migration.

The concentrations of ANP and BNP used in the present experiment are higher than the normal concentrations of plasma ANP and BNP in rats and humans.19 20 21 22 23 24 25 26 27 However, during high sodium intake28 29 30 31 or dynamic exercise,32 33 34 the levels of these peptides increase. In addition, several investigators, including our group, have previously shown that these natriuretic peptide levels are markedly high in the malignant or severe stage of rat and human hypertension.19 20 25 28 In particular, plasma BNP levels are found to be higher than plasma ANP levels in patients with severe congestive heart failure and acute myocardial infarction.35 ANP and BNP are secreted through the coronary sinus from the heart,19 20 but ANP is secreted mainly from the atria and BNP predominantly from the ventricles.14 15 36 Furthermore, vascular endothelial cells are shown to express a large number of biologically active receptors11 12 13 of ANP and BNP as well as clearance receptors. Taken together with these observations, our data raise the possibility that ANP and BNP secreted from the heart circulate into the general circulation and bind natriuretic peptide receptors in vascular endothelial cells, thereby inhibiting migration of these cells in certain pathological conditions. It remains to be further elucidated whether these natriuretic peptides inhibit endothelial cell migration in vivo in the arterial wall.

We have obtained three pieces of evidence for a causal link between cGMP production and inhibition of vascular endothelial cell migration after stimulation with FCS. First, rat ANP-(1-28) and rat BNP-45 increased cGMP levels, and these effects paralleled the inhibition of migration. Second, rat ANP-(5-25) had much weaker effects than rat ANP-(1-28) or rat BNP-45 with respect to inhibiting migration and increasing cGMP in cells stimulated with FCS. Third, a cGMP analogue inhibited FCS-stimulated migration in a concentration-dependent manner. These results suggest that ANP and BNP inhibit FCS-stimulated vascular endothelial cell migration probably through a cGMP-dependent process. Indeed, there was a significant inverse correlation between the percent increase in cellular cGMP levels and the percent decrease in migratory activity. However, further studies are necessary to elucidate the involvement of cGMP and its related systems in the inhibition by ANP and BNP of vascular endothelial cell migration.

Overall, the present work suggests that both ANP and BNP may inhibit vascular endothelial cell migration and that the increase in cellular cGMP levels is likely to be involved in this inhibition. This action may be added to natriuresis, vasodilation, and antiproliferation37 38 39 40 as yet another effect of cardiac natriuretic peptides.


*    Selected Abbreviations and Acronyms
 
ANP = atrial natriuretic peptide
BNP = brain natriuretic peptide
DMEM = Dulbecco's modified Eagle's medium
FCS = fetal calf serum
IBMX = 3-isobutyl-1-methylxanthine


*    Acknowledgments
 
The authors are grateful to Dr Nobuhiro Morisaki, Second Department of Internal Medicine, Chiba University, for his helpful instruction and to Dr Makiko Ueda, First Department of Pathology, Osaka City University, for her valuable advice.

Received December 27, 1994; first decision March 14, 1995; accepted May 30, 1995.


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 up arrowIntroduction
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 *References
 

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