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Laboratoire de Biologie Cellulaire, World Health Collaborating Center for the Development of the Endocrine Pancreas, Université Catholique de Louvain, B-1348 Louvain-La-Neuve, Belgium; * Lawson Health Research Institute, St. Joseph’s Health Care, London, ON and Departments of Medicine, Physiology and Paediatrics, University of Western Ontario, London, ON N6A 4V2, Canada
3To whom correspondence should be addressed. E-mail: reusens{at}bani.ucl.ac.be.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • low protein • endocrine pancreas • vascular endothelial growth factor • fetal liver kinase-1 • taurine
The endocrine pancreas is a richly vascularized tissue. In rodents, each islet of Langerhans receives its blood supply from one to five afferent arterioles that branch into a glomerular-like network of microvessels and form a local intra-islet portal system (1) through which blood flows from the central core of ß-cells to the non ß-cell mantle. Endocrine microvessels are wider and thinner walled than the exocrine capillaries, and possess 10 times as many fenestrations (2). The maintenance of this fenestrated endothelium requires precise homeostatic regulation.
Vascular endothelial growth factor (VEGF)3 is a dimeric glycosylated protein with structural homology to platelet-derived growth factor. VEGF is a strong mitogenic factor for endothelial cells in various in vitro and in vivo systems (3,4) and has been shown to increase the permeability of microvessels (5,6). VEGF binds with high affinity to two highly homologous tyrosine kinase receptors expressed mainly by endothelial cells: the tyrosine kinase receptor KDR for the murine homology fetal liver kinase-1 (Flk-1), also known as VEGF-R2 (7,8) and the fms-like tyrosine kinase receptor (Flt-1), also called VEGF-R1 (9).
In islets of Langerhans, strong VEGF staining was reported in ß-cells and non-ß-cells(10,11). These observations suggest that continued low level secretion of VEGF by islet cells may play a major role in the homeostasis of the rich intra-insular vasculature, in particular in the maintenance of the fenestrated endothelium (12). VEGF was found also to be weakly expressed by acinar cells in the exocrine pancreas. The two high affinity receptors for VEGF, Flt-1 and Flk-1, are also expressed in adult and fetal islets of Langerhans and in the exocrine pancreas. VEGF receptor Flk-1 is expressed by the endothelial cells (13) and by the pancreatic ductal cells during fetal development. This suggests that VEGF and its receptor might also play a role in both endocrine pancreatic organogenesis and the population dynamics of pancreatic ducts (14), especially because VEGF was shown to be mitogenic for the pancreatic ductal epithelium (10). Recently, blood vessels were shown to provide not only metabolic sustenance, but also inductive signals for endocrine pancreas development, and VEGF would be a major factor in this endothelium-endocrine cell interaction (15).
We previously described a model of protein deficiency in pregnant rats fed either a control diet (C) containing 20% protein or an isoenergetic low protein diet (LP) containing 8% protein throughout gestation. LP fetuses and neonates had a lower body weight than controls (16). The mean islet size was reduced after LP diet consumption in association with a lower rate of islet cell proliferation and a higher apoptotic rate (17,18). The insulin secretory capacity of fetal ß-cells was impaired in response to secretagogues (19). Islet blood vessel development was very sensitive to the lack of protein availability in utero. LP fetuses had a marked reduction in the islet blood vessel density (17). When the LP diet was fed until adult age, there was a 65% decrease in the islet blood flow (20). The low protein diet during gestation also greatly affected the plasma amino acid profile of dams and fetuses. Certain amino acids, especially taurine, have limited availability in the serum of fetuses from dams fed the LP diet (21). Taurine is a sulfur-containing amino acid that is best known for its conjugation with bile acids, but it is also involved in the coordination of nerve function, stabilization of the cell membrane, detoxification, antioxidant reactions and modulation of osmotic pressure (22,23). In the pancreas, taurine is highly concentrated in the islets and stimulates insulin release by fetal ß-cells in vitro (24,25). In recent investigations, we reported that taurine supplementation in vivo and in vitro can reverse many of the impairments caused by a low protein diet during fetal and neonatal life such as fetal insulin secretion, islet and ß-cell mass, endocrine apoptotic and proliferative rates (16,26). However, taurine supplementation of the LP fetuses and neonates did not restore normal body weight (16).
The present study was therefore designed to investigate the effect in vivo of taurine supplementation of a low protein diet in dams during gestation on fetal islet vascularization. We also examined whether this supplementation influenced VEGF and VEGF receptor Flk-1 expression in the fetal endocrine pancreas.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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All procedures were performed with the approval of the animal ethics committees of the Catholic University of Louvain. Four groups of gestating Wistar rats were created depending on the diet provided. A control group (C) was given a 20% protein diet and a group (LP) received an 8%, low protein diet. Both diets were isoenergetic, with energy balanced by the addition of carbohydrate. A third group was fed the control diet supplemented with 25 g/L taurine (T; Sigma Chemical, Brussels, Belgium) in the drinking water (C+T) and a final group was fed the LP diet supplemented with 25 g/L taurine (LP+T). The diets were given throughout gestation. Diets were purchased from Hope Farms (Woerden, Holland). These diets were devoid of taurine and the exact composition has been described elsewhere (27). For the reduction in protein, less casein, which is the main protein source, and less methionine were used in the LP diet. Pregnant rats from the C, LP, C+T and LP+T groups were anesthetized with pentobarbital, (55 mg/kg body) on d 21.5 of gestation (F21.5). Immunocytochemistry to determine VEGF was performed on fetal pancreata and also on pancreata of 12-, 14- and 30-d-old pups that had consumed the same diet as their dams.
Epon embedding.
Pancreata were placed in ice-cold fixative (25 g/L glutaraldehyde in 0.1 mol/L phosphate buffer, pH 7.2) for 2 h, rinsed, and postfixed in 10 g/L osmium tetroxide in phosphate buffer for 1 h. The tissue was washed in phosphate buffer, ethanol dehydrated and embedded in epon.
Paraffin embedding.
Pancreata were placed in ice-cold fixative (40 g/L paraformaldehyde and 2 g/L glutaraldehyde in 70 mmol/L PBS, pH 7.4) overnight at 4°C, followed by 4 washes at 4°C in PBS over a 48-h period, ethanol dehydrated and embedded in paraffin.
Vascularization analysis.
Three semi-thin sections (1 µm) of epon-embedded pieces were randomly cut in each pancreas and stained with toluidine blue. The areas of the islets and of the intra-insular blood vessels were measured, using NIH-Image 1.56 software in a Reichert Polyvar microscope (Wien, Austria); their ratio gave the volume density of blood vessels in the islet. For estimation of numerical density of blood vessels, the number of capillaries was counted in each islet and related to the islet area. For the morphometrical studies, six fetuses were used in each group.
Immunocytochemistry.
Immunocytochemistry was performed on paraffin serial sections of 7 µm in fixed pancreata to localize VEGF, VEGF receptor Flk-1 and insulin using a modified avidin-biotin peroxidase method (??B0 ). Slides were incubated overnight at 4°C in a humidified chamber with rabbit anti-VEGF antibody (1:500 dilution) (Pharminagen, Mississauga, Canada), rabbit anti-Flk-1 antibody (1:200 dilution) (Santa Cruz Biotechnology, Santa Cruz, CA) or mouse anti-insulin antibody (1:6000 dilution) (Novo Nordisk, Copenhagen, Denmark). All antisera were diluted in 0.01 mol/L PBS (pH 7.5) containing 20 g/L bovine serum albumin and 1 g/L sodium azide (100 µL/tissue section). Goat anti-rabbit IgG (1:100 dilution) (Vector Laboratories, Burlingame, CA), sheep anti-rabbit IgG (1:500 dilution) and sheep anti-mouse IgG (1:1500 dilution) (Amersham, Bergrand, Netherlands) were used as secondary antibodies. In addition, for every ligand, negative controls were performed by omitting primary antiserum. In each case staining was abolished. Tissue sections were counter-stained with Carrazi’s hematoxylin.
Morphometrical analysis.
To quantify the relative presence of VEGF, morphometric analysis was performed using a Zeiss transmission light microscope at a magnification of X250 or X400. Analyses were performed with Northern Eclipse version 2.0 morphometric analysis software (Empix Imaging, Mississauga, Canada). The percentage of islet cells immunopositive for the protein was calculated at each age from up to three noncontiguous sections of each pancreas. Sections chosen contained at least five islets each and pancreata of five rats were examined for each group. Individual cell area and total areas of immunoreactive cells within islets were circled for image analysis and selected by gray-level threshold. To quantify the percentage of islet cells and duct cells positive to VEGF receptor Flk-1, manual counting was performed using NIH-image 1–16 software. Values are expressed as a percentage of immunoreactivity.
Statistical analysis.
Statistical comparisons were made using one or two-way ANOVA as specified, followed by Scheffé’s test.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Volume density of islet blood vessels was measured on semi-thin sections in pancreata (Fig. 1) of 21.5-d-old rat fetuses. Vascular density was severely decreased (P < 0.01) in LP fetal islets compared with controls. Vascular density was not affected by taurine supplementation in C+T islets, whereas in LP+T islets, it was comparable to that of controls (P > 0.05). Thus, vascular density was completely restored by taurine supplementation compared with the LP group (P < 0.01) (Fig. 2A).
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VEGF in islet cells.
A diffuse immunocytochemical staining for VEGF was found in the exocrine parts of sections from pancreata of both C and LP fetuses. A much denser staining was present in the islets of Langerhans of all groups, colocalizing with the insulin immunostaining (Fig. 3A, B). The proportion of islet area positive to VEGF is reported in Figure 4. This proportion was reduced (P < 0.05) in LP fetuses and neonates compared with controls at all days analyzed. Taurine supplementation increased (P < 0.01) the immunoreactivity for VEGF in C+T islets in fetuses but not after birth. In islets from LP+T fetuses, it was significantly and completely restored at all ages analyzed (P < 0.01). We also noted a progressive increase in VEGF-positive cells from fetal age 21.5 to postnatal age 30 d.
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A very weak immunocytochemical staining for VEGF receptor Flk-1 was found in the exocrine parts of sections from pancreata of both C and LP fetuses. A much denser staining was present in the islet cell cytoplasm of the four groups. Immunoreactivity for VEGF receptor Flk-1 was also observed in cells of the ductal epithelium (Fig. 5). The percentage of islet cells immunopositive to VEGF receptor Flk-1 was measured in each group. We found that immunostaining for Flk-1 was decreased in islets from LP fetuses compared with C fetuses (P < 0.01) (Fig. 6A). Maternal taurine supplementation did not affect the number of islet cells immunoreactive to Flk-1 in islets of C+T fetuses, whereas it enhanced that of islets of LP+T fetuses (P < 0.05). We measured the percentage of duct cells immunopositive to the VEGF receptor Flk-1 of C and LP fetuses. Ducts considered for this experiment were those in close contact with the islets. This percentage of ductal cells was greater (P < 0.01) in fetuses of LP rats than in C rats (Fig. 6B). Taurine supplementation did not affect on the number of ductal cells immunoreactive to Flk-1 in either C or LP fetuses.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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In the present study, the volume density of blood vessels on the last day of gestation was lower in islets from LP-fed rats in association with a reduction in their number. Interactions between pancreatic and endothelial cells occur long before islets are functionally mature and are maintained throughout islet formation (15). It is unclear, however, whether the alterations in the LP vascular system are the cause or the consequence of alterations in the number, morphology and function of islet cells.
In searching for factors that could regulate the vascular system, we investigated VEGF and its receptor Flk-1 in the endocrine pancreas. We demonstrated an intense immunostaining for VEGF in the central part of the islets of Langerhans colocalizing with the ß-cells. This finding agrees with previous results demonstrating the presence of VEGF in the endocrine pancreas (10). We described also, for the first time, the progressive increase in VEGF expression in the islet cells after birth in all groups. VEGF and its receptor Flt-1 were also present in ß-cell lines derived from rat tumors, namely, RIN m5F-2A and INS-1, as well as the mouse insulinoma-derived cell line MIN 6 (11,28). We know from recent studies that VEGF may have a role in ß-cell maturation from ductal precursor cells because its receptor Flk-1 is found in ductal cells, whereas exogenous VEGF stimulates their proliferation (24,29). We investigated the presence of VEGF receptor Flk-1 in fetal islets, and Flk-1 immunostaining occurred, mainly in ß-cells. Thus, locally produced VEGF might have several roles in the regeneration of the pancreas, both directly by stimulating cell maturation in the ductal epithelium and in islets, and indirectly by neoformation of capillaries (29).
The proportion of VEGF positive cells was reduced in fetal islets from LP fed-rats compared with controls, suggesting that the impaired vasculature induced by the LP diet during fetal life could be a consequence of the reduction in the production of VEGF by surrounding endocrine cells. When the LP diet continued to be fed after birth, this VEGF-positive cell population remained low. The percentage of islet cells immunopositive for the VEGF receptor Flk-1 was lower in LP fetuses than in controls. There was also a dense immunostaining for Flk-1 in duct cells, as reported by others (13,14). Ducts from LP-fed rats had an enhanced number of cells expressing the VEGF receptor Flk-1. This result suggests an up-regulation of Flk-1 production in duct cells as a reaction to the decreased endocrine cell mass induced by the LP diet. However, this mechanism for enhancing islet neogenesis was probably suboptimal because VEGF production by LP endocrine cells was too low.
Alterations in islet blood capillaries in LP islets could also be due to other changes in the nutritional and/or hormonal status of fetuses. Decreased nutrient availability, such as of amino acids, may play a role in the reduction of vascularization (30,31). Insulin is considered to be a growth factor for endothelial cells, especially in microvessels (32) and pancreatic insulin content was lower in the fetuses of LP-fed rats, (17). Insulin-like growth factor (IGF) stimulates the proliferation of endothelial cells and blood vessel formation (33). Insulin and IGF should be elevated in the surrounding environment of the islet blood vessel because of the vicinity of insulin-secreting cells and IGF-containing cells as shown by Petrik et al. (18). Plasma levels of IGF (34,35) and IGF-1 expression in islet cells were also reduced in LP fetuses (16,18). Endothelial cells harbor instructive signals including VEGF, which induces endocrine pancreatic cell differentiation and morphogenesis (15); however, VEGF can exert its stimulatory effect on endothelial cell proliferation only if there is sufficient IGF-1, as demonstrated in IGF-1 null mice (36). Therefore, lower IGF levels may be responsible in part for the observed reduction of islet vascularization via VEGF.
Taurine was one of the amino acids most reduced in fetal serum in this LP diet model (21). Taurine supplementation and its normalization in the blood circulation (26) completely restored the decreased blood vessel volume density and number in fetal islets induced by the LP diet. The effect of taurine on islet vascularization could be due to a beneficial action on endothelial cells. Indeed, taurine has been suggested to play a cytoprotective role in human umbilical endothelial cells (37) and in human vascular endothelial cells (38) because of its ability to prevent stimuli-induced and high glucose–induced apoptosis. Taurine also had a protective effect against IL-2–mediated endothelial cell injury in vitro (39). The source of protein used in these experiments was casein. Casein is the source for less that the half of the cysteine required during gestation (40). Taurine is derived from cysteine and methionine and no methionine was added to this diet. Our protein-deficient diet reduced taurine in the maternal and fetal plasma as well in the fetal islets (21). Supplementing a protein-deficient diet with taurine would reduce the demand for cysteine, which would reduce the flux through the transulfuration pathway and therefore lower homocysteine production, an effect seen with methionine supplementation (41). Small increases in the levels of homocysteine have adverse effects on endothelial cell function (42). Thus, taurine supplementation may have reduced the level of homocysteine, which in turn may have had a beneficial effect on endothelial cells.
In addition, taurine could act either directly or indirectly by enhancing growth factor production. We recently demonstrated that taurine supplementation of the maternal diet restored normal IGF-II expression in islet cells of fetuses of LP-fed rats (16). IGF were reported to protect various cell types against apoptosis (43), and were shown to be stimulatory factors of endothelial cell proliferation and blood vessel formation (33,36). We demonstrated here that taurine restored VEGF expression in LP-fed pups at all ages analyzed. In the retina of diabetic rats, taurine attenuated VEGF up-regulation and thus normalized it via mechanisms that are poorly understood but that appear to be related to antioxidative defense (44). In our LP rats, taurine also helped normalize the VEGF presence by increasing the number of VEGF-positive islet cells. The mechanisms involved here warrant further research. Oxidative stress is not likely to be a factor in this restoration of VEGF expression in the fetus because neither the maternal LP diet nor taurine supplementation modified the number of islet cells expressing inducible nitric oxide synthase (16,18).
Taurine supplementation restored the number of Flk-1 positive islet cells, but the amino acid does not appear to regulate the presence of the receptor in duct cells.
In conclusion, we demonstrated the importance of taurine during fetal vascular and endocrine system development. These findings might have relevance for humans because in type 1 and 2 diabetes, in which ß-cell mass and vascularization are impaired, plasma taurine concentration is dramatically reduced (45).
In the present study, consequent to LP diet intake early in life, the endocrine vascular system was damaged and the presence of VEGF and Flk-1 in the islet cells was decreased. Their expression was restored by taurine. More investigation is required to determine the molecular mechanisms underlying the effect of taurine on VEGF and Flk-1 expression. Our data also suggest that VEGF is a major stimulus of islet vascularization, which would contribute to control the ß-cell mass in the fetus.
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FOOTNOTES |
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2 Supported by a grant from the Parthenon Trust, London, UK, the Fond National de Recherche Scientifique, Belgium and the European Union (QLTR-2000–00083).
4 Abbreviations used: C, control; C+T, control supplemented with taurine; Flk-1, fetal liver kinase-1; Flt-1, fms-like tyrosine kinase; IGF, insulin-like growth factor; LP, low protein; LP+T, low protein supplemented with taurine; VEGF, vascular endothelial growth factor.
Manuscript received 9 April 2003. Initial review completed 4 May 2003. Revision accepted 3 July 2003.
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  B. Coupe, I. Grit, D. Darmaun, and P. Parnet The timing of "catch-up growth" affects metabolism and appetite regulation in male rats born with intrauterine growth restriction Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2009; 297(3): R813 - R824. [Abstract] [Full Text] [PDF]
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 A. Chamson-Reig, E. J Arany, K. Summers, and D. J Hill A low protein diet in early life delays the onset of diabetes in the non-obese diabetic mouse J. Endocrinol., May 1, 2009; 201(2): 231 - 239. [Abstract] [Full Text] [PDF]
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 I. Ueki and M. H. Stipanuk Enzymes of the Taurine Biosynthetic Pathway Are Expressed in Rat Mammary Gland J. Nutr., August 1, 2007; 137(8): 1887 - 1894. [Abstract] [Full Text] [PDF]
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X. Wang, L. Liang, and L. Du The effects of intrauterine undernutrition on pancreas ghrelin and insulin expression in neonate rats J. Endocrinol., July 1, 2007; 194(1): 121 - 129. [Abstract] [Full Text] [PDF]
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 K. Hultman, C. Alexanderson, L. Manneras, M. Sandberg, A. Holmang, and T. Jansson Maternal taurine supplementation in the late pregnant rat stimulates postnatal growth and induces obesity and insulin resistance in adult offspring J. Physiol., March 15, 2007; 579(3): 823 - 833. [Abstract] [Full Text] [PDF]
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A. Chamson-Reig, S. M Thyssen, E. Arany, and D. J Hill Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific. J. Endocrinol., October 1, 2006; 191(1): 83 - 92. [Abstract] [Full Text] [PDF]
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W. D. Rees, F. A. Wilson, and C. A. Maloney Sulfur Amino Acid Metabolism in Pregnancy: The Impact of Methionine in the Maternal Diet J. Nutr., June 1, 2006; 136(6): 1701S - 1705S. [Abstract] [Full Text] [PDF]
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 M. Thamotharan, B.-C. Shin, D. T. Suddirikku, S. Thamotharan, M. Garg, and S. U. Devaskar GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E935 - E947. [Abstract] [Full Text] [PDF]
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 I. C. Mcmillen and J. S. Robinson Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming Physiol Rev, April 1, 2005; 85(2): 571 - 633. [Abstract] [Full Text] [PDF]
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 E. A. Joanette, B. Reusens, E. Arany, S. Thyssen, R. C. Remacle, and D. J. Hill Low-Protein Diet during Early Life Causes a Reduction in the Frequency of Cells Immunopositive for Nestin and CD34 in Both Pancreatic Ducts and Islets in the Rat Endocrinology, June 1, 2004; 145(6): 3004 - 3013. [Abstract] [Full Text] [PDF]
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