Progesterone maintains large rat granulosa cell viability indirectly by stimulating small granulosa cells to synthesize basic fibroblast growth factor

Ovarian follicles are composed of small and large granulosa cells (GCs). Since progesterone (P4) inhibits large GCs from undergoing apoptosis, studies were designed to determine whether both sizes of GCs bind P4. These studies revealed that fluorescein isothiocyanate-BSA-P4 bound only to the surface membranes of small GCs. This binding was steroid-specific and inhibited by an antibody directed against the ligand-binding domain of the nuclear P4 receptor (PR). In addition, a cell-impermeable derivative of P4, BSA-conjugated P4, was as effective as P4 in preventing apoptosis. Quantitative in situ hybridization studies showed that P4 increased the relative amount of basic fibroblast growth factor (bFGF) mRNA expressed per cell as well as the percentage of small GCs that expressed bFGF. To determine whether the anti-apoptotic action of P4 was mediated by bFGF, GCs were cultured in control medium supplemented with either P4, a neutralizing antibody to bFGF, or both P4 and the bFGF antibody. The results from this study demonstrated that P4 suppressed apoptosis and that this effect was attenuated in presence of the bFGF antibody. Basic FGF also prevented GC apoptosis, and its action was not influenced by either the PR antagonist (RU-486), an inhibitor of P4 synthesis (aminoglutethimide), or a PR antibody. Finally, FGF receptors were detected on both small and large GCs. Collectively, these data support the hypothesis that P4 acts through a putative membrane receptor on small GCs to stimulate the synthesis of bFGF. Basic FGF then activates its receptors within large GCs, and this initiates a signal transduction pathway that maintains large GC viability.     

Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis

Angiogenesis is a possible target in the treatment of human gliomas. To evaluate the role of 3 growth factors, vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF) and basic fibroblast growth factor (bFGF), in the angiogenic cascade, we determined their levels in extracts of 71 gliomas by enzyme-linked immunosorbent assay (ELISA). The levels of bFGF were only marginally different between gliomas of World Health Organization (WHO) grade II (low grade) and grades III and IV (high grade). In contrast, the mean concentrations of VEGF were 11-fold higher in high-grade tumors and those of HGF/SF 7-fold, respectively. Both were highly significantly correlated with microvessel density (p < 0.001) as determined by immunostaining for factor VIII-related antigen. In addition, VEGF and HGF/SF appeared to be independent predictive parameters for glioma microvessel density as determined by multiple regression analysis. We measured the capacity of all 3 factors to induce endothelial tube formation in a collagen gel. In this assay, bFGF was found to be an essential cofactor with which VEGF as well as HGF/SF were able to synergize independently. According to the concentrations of angiogenic factors, extracts from high-grade tumors were significantly more potent in the tube formation assay than the low-grade extracts (p = 0.02). Adding neutralizing antibodies to bFGF, VEGF and HGF/SF together with the extracts, tube formation was inhibited by up to 98%, 62% and 54%, respectively. Our findings suggest that bFGF is an essential cofactor for angiogenesis in gliomas, but in itself is insufficient as it is present already in the sparsely vascularized low-grade tumors. Upon induction of angiogenesis in high-grade tumors, bFGF may synergize with rising levels of not only VEGF but possibly also with HGF/SF, which appears here to be an independent angiogenic factor.     

Immunolocalization of basic fibroblast growth factor and fibroblast growth factor receptor-1 and receptor-2 in rat cranial sutures

Craniosynostosis is a common disorder with an unknown etiology. Recent genetic mapping studies have demonstrated a strong linkage between several familial craniosynostotic syndromes and mutations in fibroblast growth factor receptor 1 (FGF-R1) and 2 (FGF-R2). The purpose of this experiment was to investigate by immunohistochemistry the protein production of these receptors as well as of their most prevalent ligand, basic fibroblast growth factor (bFGF), before, during, and after sutural fusion in rat cranial sutures. The posterior frontal (normally fuses between postnatal days 12 and 22) and sagittal (remains patent) sutures of embryonic day 20 and neonatal days 6, 12, 17, 22, and 62 (n = 3 per group) were harvested, fixed, and decalcified. Five-micrometer sections were stained with polyclonal antibodies against bFGF, FGF-R1, and FGF-R2, and patterns of immunohistochemical staining were assessed by independent reviewers. Our results indicate that increased bFGF production correlates temporally with suture fusion, with increased staining of the dura underneath the fusing suture prior to fusion followed by increased staining within osteoblasts and sutural cells during fusion. FGF-R1 and, to a lesser extent FGF-R2 immunostaining revealed a different pattern of localization with increased immunostaining within the patent sagittal suture at these time points. These results implicate bFGF in the regulation of sutural fusion and may imply autoregulatory mechanisms in fibroblast growth factor receptor expression.     

Serum levels of basic fibroblast growth factor in acute myocardial infarction

As it has been reported that basic fibroblast growth factor (bFGF) is a circulating peptide and bFGF gene expression is increased after myocardial ischemia, this study was designed to investigate the serum levels of bFGF in patients with acute myocardial infarction (AMI). Using a bFGF enzyme-linked immunoassay, bFGF levels were determined in venous blood of 15 patients with AMI on admission, at 10 days, and 30 days after infarction, and of 15 age-matched healthy volunteers who were used as controls. bFGF serum levels on admission were similar to normal values (7.48 +/- 2.3 vs 8.14 +/- 2.9 pg/ml). However, they significantly increased (16.82 +/- 3.4 pg/ml; p <0.05) 10 days after the onset of AMI, and at 30 days they returned to baseline (7.07 +/- 2.9 pg/ml). The increased bFGF levels at the second week post AMI suggest that bFGF plays an important role in mediating the development of coronary collateral circulation after myocardial ischemia in humans.     

Expression of basic fibroblast growth factor and its mRNA in advanced ovarian cancers

Seventeen patients with a mean age of 7.33 (range 2.7-12.7) years with Rett syndrome (a progressive neurological disorder that occurs mainly in females) were evaluated for oral manifestations and habits. The most frequent habits were digit/hand sucking and/or biting (17/17), bruxism (14/17), mouth breathing (7/17), drooling (5/17), and tongue thrusting (5/17). Gingivitis (13/17) was the most common alteration of soft tissues. Only 2.7% of tooth surfaces were decayed. Nonphysiological dental attrition was present in 71% (12/17) of the children. Palatal shelving could be observed in 53% (9/17) of the children, probably related to the digit/hand sucking and/or biting habits. A high prevalence of anterior open bite (9/17) was observed. No patients exhibited anomalies of tooth number, size, form, structure, or eruption.     

Elevated levels of basic fibroblast growth factor in patients with limb ischemia

Basic fibroblast growth factor (bFGF), a prototypic member of a family of heparin-binding growth factors, is angiogenic both in vitro and in vivo. Increased levels and activity of bFGF have been documented in a variety of diseases, including tumors. We sought to determine whether bFGF might be similarly elevated in patients with clinical evidence of limb ischemia. Serum was obtained at the time of percutaneous revascularization from patients with symptomatic peripheral vascular disease (46 procedures were performed on 40 patients). An enzyme-linked immunoassay specific for bFGF was used (limit of detection, 1 pg/ml; range in normal subjects, 0 to 5 pg/ml). Among the 40 patients (28 men, 12 women, mean age 70 years) studied, elevated circulating bFGF (> or = 10 pg/ml) was detected in 36 samples (78%); levels ranged from 10 to 310 pg/ml (mean +/- SEM = 62 +/- 12). In 16 (89%) of 18 patients with both rest pain and nonhealing ischemic ulcers, serum bFGF levels were elevated up to 30 times normal values. In conclusion, circulating levels of bFGF are elevated in patients with vascular insufficiency and may reflect a physiologic response to limb ischemia.     

Glucocorticoids differentially increase nerve growth factor and basic fibroblast growth factor expression in the rat brain

Adrenocorticotropin hormone (ACTH) and adrenal steroids may influence trophic processes operative in neuronal plasticity. Because nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) participate in neuronal trophism, we have investigated whether adrenal steroids induce the expression of these two trophic factors in the rat brain. The systemic administration of dexamethasone (DEX) elicited a rapid (within 3 hr) and sustained accumulation of bFGF and NGF mRNA in the cerebral cortex and hippocampus. Regional studies showed that DEX increases bFGF but not NGF mRNA in the cerebellum, striatum, and hypothalamus. In situ hybridization studies revealed that DEX increases NGF mRNA in superficial layers of the cerebral cortex and in the dentate gyrus of the hippocampus, and bFGF mRNA throughout the brain, suggesting that DEX induces NGF mRNA in neurons and bFGF in glial cells. ACTH administered systemically elicited a temporal and regional induction in NGF and bFGF mRNA similar to that obtained with DEX. Increases in NGF and bFGF mRNAs were also observed after administration of corticosterone and, albeit to a lesser extent, aldosterone, suggesting that the pituitary-adrenocortical axis plays an important role in the regulation of NGF and bFGF expression in the brain. Our data suggest that NGF and bFGF represent a link by which the adrenal cortical system can exert trophic action on the CNS.     

Negative inotropic effect of basic fibroblast growth factor on adult rat cardiac myocyte

BACKGROUND: Basic fibroblast growth factor (bFGF) is highly expressed in the myocardium in some cardiac disorders, such as ischemia-reperfusion and cardiac allograft rejection. However, whether bFGF has any effects on myocardial contraction is unknown. METHODS AND RESULTS: We examined the effects of bFGF on myocardial contractility using isolated adult rat cardiac myocyte preparations. bFGF exerted a direct negative inotropic effect that was concentration and time dependent. The pretreatment of myocytes with a neutralizing anti-bFGF antibody (100 ng/mL) abolished the negative inotropic effects of bFGF (100 ng/mL). Platelet-derived growth factor (12.5 ng/mL) and transforming growth factor-beta (1 ng/mL) did not exert such effects, which indicated that bFGF-induced negative inotropism was considered to be specific for this growth factor. bFGF decreased the peak intracellular Ca2+ transient by 46% during systole. The enhanced production of nitric oxide was unlikely to be responsible for the bFGF-induced negative inotropic effect. CONCLUSIONS: bFGF, primarily a potent growth promoter, produced acute negative inotropic effects in the adult cardiac myocyte that could have resulted from alterations in intracellular Ca2+ homeostasis. The negative inotropic effect of bFGF may contribute to myocardial dysfunction associated with ischemia-reperfusion injury and heart transplant rejection.     

Differential induction of nerve growth factor and basic fibroblast growth factor mRNA in neonatal and aged rat brain

Stimulation of glucocorticoid or beta-adrenergic receptors (BAR) has been shown to increase nerve growth factor (NGF) biosynthesis in adult rat brain. Little is known about the role of these receptors in the regulation of NGF expression in neonatal and aged brain. We have examined the effect of the synthetic glucocorticoid dexamethasone (DEX) and the BAR agonist clenbuterol (CLE) on the levels of NGF mRNA in neonatal (8 day old), adult (3 month old) and aged (24 month old) rats. By 3 h, DEX (0.5 mg/kg, s.c.) evoked a comparable increase in NGF mRNA in the cerebral cortex and hippocampus in both 8-day and 3-month-old rats. In contrast, CLE (10 mg/kg, i.p.) failed to change NGF mRNA levels in neonatal rats, while increasing (2-3-fold) NGF mRNA levels in the cerebral cortex of adult rats. In 24-month-old rats, both DEX and CLE elicited only a modest increase in NGF mRNA. This increase was, however, anatomically and temporally similar to that observed in adult animals. The weak effect of DEX or CLE was not related to a down-regulation of receptor function because both DEX and CLE were able to elicit a comparable increase in the mRNA levels for basic fibroblast growth factor (FGF2) in neonatal, adult and aged rat brain. Our data demonstrate that induction of NGF expression by neurotransmitter/hormone receptor activation varies throughout life and suggest that pharmacological agents might be useful tools to enhance trophic support in aging.     

Effects of basic fibroblast growth factor on anoxia/reoxygenation injury of rat neonatal cardiomyocytes

The effects of basic fibroblast growth factor (bFGF) on anoxia/reoxygenation (A/R) injury and protein kinase C (PKC) activity were studied on a model of A/R injury of neonatal rat cardiomyocytes to investigate the possibility of its using as a substrate for pharmacological preconditioning. The data indicated that bFGF improved the viability of cardiomyocytes, lowered the deplection of ATP and leakage of intracellular lactate dehydrogenase (LDH) in a concentration-dependent manner. PKC inhibitor, H7, completely abolished the protective effects. It was also found that bFGF directely activated PKC in cardiomyocytes in a time course similar to that in hypoxic preconditioning. The data suggested that the protective effect of bFGF on cardiomyocyte A/R injury might be mediated by PKC.     

Neuronal survival and calcium influx induced by basic fibroblast growth factor in chick ciliary ganglion neurons

Basic fibroblast growth factor (bFGF/FGF2) exhibits widespread biological activities in the nervous system. However, little is known about the cascade of intracellular events that links the activation of its tyrosine kinase receptors to these effects. Here we report that, in ciliary ganglion neurons from chick embryo, this trophic factor significantly enhanced neuronal survival. The percentage of surviving neurons was reduced when intracellular calcium was chelated by adding a membrane-permeable BAPTA ester to the culture medium, while antagonists of L- and N-type voltage-dependent calcium channels were ineffective. The ionic signals in response to bFGF stimulation have been studied using cytofluorimetric and patch-clamp techniques. In single-cell Fura-2 measurements, bFGF elicited a long lasting rise of the cytosolic calcium concentration that was dependent on [Ca2+]o. In whole-cell experiments, we observed a reversible depolarization of the membrane resting potential and an inward cationic current. Single channel experiments, performed in the cell-attached configuration, provide evidence for the activation of two families of Ca2+-permeable cationic channels. Moreover, inositol 1,4,5-trisphosphate opens channels with similar properties, suggesting that this cytosolic messenger can be responsible for the calcium influx induced by bFGF.     

Binding of basic fibroblast growth factor to fibrinogen and fibrin

Fibrin is formed at sites of tissue injury and provides the temporary matrix needed to support the initial endothelial cell responses needed for vessel repair. Basic fibroblast growth factor (bFGF) also acts at sites of injury and stimulates similar vascular cell responses. We have, therefore, investigated whether there are specific interactions between bFGF and fibrinogen and fibrin that could play a role in coordinating these actions. Binding studies were performed using bFGF immobilized on Sepharose beads and soluble 125I-labeled fibrinogen and also using Sepharose-immobilized fibrinogen and soluble 125I-bFGF. Both systems demonstrated specific and saturable binding. Scatchard analysis indicated two classes of binding sites for each with Kd values of 1.3 and 260 nM using immobilized bFGF; and Kd values of 0.9 and 70 nM using immobilized fibrinogen. After conversion of Sepharose-immobilized fibrinogen to fibrin by treatment with thrombin, bFGF also demonstrated specific and saturable binding with two classes of binding sites having Kd values of 0.13 and 83 nM. Fibrin binding was also investigated by clotting a solution of bFGF and fibrinogen, and two classes of binding sites were demonstrated using this system with Kd values of 0.8 and 261 nM. The maximum molar binding ratios of bFGF to fibrinogen were between 2.0 and 4.0 with the four binding systems. We conclude that bFGF binds specifically and saturably to fibrinogen and fibrin with high affinity, and this may have implications regarding the localization of its effect at sites of tissue injury.     

Immunohistochemical localization of basic fibroblast growth factor (bFGF) within growing and atretic mouse ovarian follicles

Basic fibroblast growth factor is a biologically active peptide with a strong affinity for heparin. This growth factor has been previously shown to be mitogenic for a variety of mesoderm and neuroectoderm-derived cells. The immunohistochemical localization of basic FGF within mouse growing and atretic ovarian follicles is presented in the study. Ovarian tissue samples were obtained either (a) randomly from mice housed in a controlled light environment or (b) following the administration of exogenous gonadotropins to stimulate follicle development. Ovarian samples were fixed in Bouin's fluid for no longer than 18 h. Following fixation and paraffin embedding, sections were exposed to a primary antibody made in rabbits against either (a) human recombinant basic FGF or (b) the 1-24 synthetic fragment of bovine basic FGF. The primary antibody was followed by biotinylated goat anti-rabbit IgG and a biotin-avidin-peroxidase complex. There were no differences in the immunolocalization of basic FGF using either source of primary antibody or between randomly obtained ovarian samples and those obtained from mice given exogenous gonadotropins. Basic FGF was immunolocalized in follicle basal laminae and was also closely associated with individual follicle cells during all stages of ovarian follicle development. Basic FGF was absent in the theca interna, oocyte cytoplasm, zona pellucida and follicle fluid of normal growing follicles. Individual corpora luteal cells were surrounded by basic FGF but lacked cytoplasmic staining. Atretic follicles exhibited staining patterns similar to their respective stage of follicle development. However, when present, follicle fluid within atretic follicles was strongly positive for basic FGF. These results indicate that basic FGF may be an important factor involved in intraovarian control mechanisms.     

Differential effects of hepatocyte growth factor isoforms on epithelial and endothelial tubulogenesis

Pigs are emerging as the most likely providers of genetically engineered organs and cells for the purpose of clinical xenotransplantation. Introduction of clinical trials has been delayed primarily by uncertainties regarding the risk of swine pathogen transmission that could harm the recipient. The concern that xenotransplantation carries the potential for a new epidemic has been highlighted by recent experiences with both bovine spongiform encephalopathy and human immunodeficiency diseases. As clinical trials have been postponed and xenotransplantation teams are working actively to gather data for an estimation of the risk, this review provides the reader with a state-of-the-art estimation of the microbiological hazards related to xenotransplantation of porcine organs to man. Particular emphasis is put on viral and retroviral hazards. Both current diagnostic tools and those under development are described, along with breeding strategies to provide donor animals that would not put the recipient or the general population at risk.     

Effects of modulation of basic fibroblast growth factor on tumor growth in vivo

BACKGROUND: Recombinant human basic fibroblast growth factor (rHu-bFGF) is known to stimulate proliferation in some tumor cells and to modulate tumor vascularization. PURPOSE: The purpose of this study was to examine the possible role of this agent in the development of tumors. The study was designed to determine the effects of modulating bFGF activity in vivo in tumor models from cell lines with different responses to bFGF and with different content and receptor levels of bFGF. METHODS: Two tumor cell lines (human DLD-2 colon carcinoma and rat C6 glioma) were characterized for bFGF content and bFGF receptor levels by Western blot analysis in cultured cells and by studies of [125I]rHu-bFGF binding to sections from xenografts grown in nude mice. Tumor cell proliferation was monitored after treatment with rHu-bFGF or the DG2 or DE6 IgG monoclonal antibody to rHu-bFGF in culture and in vivo. RESULTS: C6 cells exhibited 7800 high-affinity receptors for rHu-bFGF per cell (dissociation constant [Kd] = 46 pM), while DLD-2 cells lacked high-affinity receptors. rHu-bFGF stimulated [3H]thymidine uptake by C6 cells, but the addition of DG2 IgG prevented this stimulation; rHu-bFGF had no effect on [3H]thymidine incorporation by DLD-2 cells. C6 cells had higher levels of immunoreactive bFGF than did DLD-2 cells. The xenografts from both cell lines exhibited high-affinity [125I]rHu-bFGF binding that was concentrated on vascular-like structures. rHu-bFGF at a dosage of 0.25 mg/kg given intraperitoneally daily for 18 days caused a twofold increase in DLD-2 tumor weight but had little effect on the growth of C6 xenografts. In contrast, daily intravenous injections of DG2 IgG given to mice had no effect on DLD-2 tumor growth but reduced growth of C6 tumors by approximately 30%--a statistically significant difference. CONCLUSIONS: The addition of exogenous rHu-bFGF or of a neutralizing antibody resulted in significant alterations in tumor growth in vivo, which were specific for tumor type and bFGF characteristics. While some of these effects may be mediated by the bFGF-responsive endothelial cells of the tumor vasculature (DLD-2 colon carcinoma), others may result from inhibition of bFGF-dependent tumor cell proliferation (C6 glioma). IMPLICATIONS: Studies that measure tumor blood flow are necessary to confirm that these effects are mediated by changes in tumor vasculature.     

Expression of the angiogenic factors, basic fibroblast growth factor and vascular endothelial growth factor, in the ovary

In adult tissues, vascular growth (angiogenesis) occurs normally during tissue repair, such as in the healing of wounds and fractures. Inappropriate vascular growth is associated with various pathological conditions. These conditions include tumor growth, retinopathies, hemangiomas, fibroses, and rheumatoid arthritis in the case of rampant vascular growth and nonhealing wounds and fractures in the case of inadequate vascular growth. The female reproductive organs exhibit dramatic, periodic growth and regression, accompanied by equally dramatic changes in their rates of blood flow. Thus, it is not surprising that they are some of the few adult tissues in which angiogenesis occurs as a normal process. Ovarian follicles and corpora lutea contain and produce angiogenic factors. These angiogenic factors bind heparin and seem to belong to the fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) families of proteins. Based on our studies of the pattern of expression of FGF and its major receptors in bovine, ovine, and porcine corpora lutea, we have suggested that FGF may influence not only luteal cell proliferation but also cell death, thereby regulating cell turnover in the luteal vascular and nonvascular compartments. In addition, we recently have shown that luteal expression of VEGF is greatest during the early luteal phase, coincident with luteal vascularization. Moreover, VEGF is present exclusively in luteal connective tissue and perivascular (arteriolar smooth muscle and capillary pericyte) cells. In fact, the first thecal-derived cells to invade the granulosa-derived regions immediately after ovulation seem to be VEGF-containing pericytes. We have therefore hypothesized that ovarian pericytes play a key role in vascularization of developing follicles and corpora lutea. Further understanding of the specific physiological roles of these factors in follicular and luteal growth, development, and function will ultimately lead to improved methods of regulating fertility.     

Immunohistochemical profile of basic fibroblast growth factor and heparan sulphate in adult rat mandibular condylar cartilage

Basic fibroblast growth factor (bFGF) and heparan sulphate (HS) were detected immunohistochemically in mandibular condylar cartilage, and the findings compared with those on epiphyseal articular cartilage. In the condylar cartilage, both bFGF and HS were localized in chondrocytes throughout the various zones including the fibrous, proliferative, mature-cell and hypertrophic zones: bFGF immunostaining was most significant in the proliferative and mature-cell zones, while intense staining for HS was found mainly in the hypertrophic zone. Immunoreaction for bFGF was detected in the nuclei of chondrocytes, whereas HS staining was observed in the cytoplasm. In articular cartilage, only chondrocytes beneath the superficial zone (intermediate zone) demonstrated both bFGF and HS immunoreactivities. Chondrocytes in the deeper calcifying region of the articular cartilage did not immunoreact for either bFGF or HS. These findings suggest that, in contrast to the epiphyseal articular cartilage, a continuous bFGF-mediated remodelling of cells and matrix takes place in mandibular condylar cartilage during the process of endochondral ossification.     

Thecal cell-granulosa cell interactions involve a positive feedback loop among keratinocyte growth factor, hepatocyte growth factor, and Kit ligand during ovarian follicular development

Interactions between mesenchymal-derived thecal cells and epithelial-derived granulosa cells are essential for follicular development in the ovary. These mesenchymal-epithelial cell interactions are in part mediated by keratinocyte growth factor (KGF), hepatocyte growth factor (HGF), and Kit ligand (KL). This study investigates the hypothesis that thecal cell-derived growth factors (e.g. KGF and HGF) regulate granulosa cell function, and granulosa cell-derived growth factors (e.g. KL) regulate thecal cell function. Gonadotropin regulation of this cell-cell interaction is also examined. Sensitive quantitative RT-PCR assays were used to analyze gene expression of KGF, HGF, and KL in the ovary. Thecal cell-derived KGF and HGF stimulated KL expression in bovine granulosa cells. Granulosa cell-derived KL stimulated KGF and HGF expression in bovine thecal cells. These results suggest that thecal and granulosa cells interact in a positive feedback loop mediated by KGF, HGF, and KL. Previous studies have suggested that gonadotropins (i.e. FSH and LH) regulate locally produced growth factor expression in the ovary. Treatment of bovine granulosa cells with FSH and hCG (a LH agonist) directly stimulated KL expression. The LH agonist hCG was also found to stimulate both KGF and HGF expression in thecal cells. The actions of gonadotropins on follicular development may in part be indirectly regulated by KL, KGF, and HGF expression. A novel positive feedback loop was identified between thecal cells and granulosa cells that is mediated by KL, KGF, and HGF. Thecal cell-derived KGF and HGF can stimulate granulosa cell-derived KL expression, and KL, in turn, can stimulate thecal cell-derived KGF and HGF expression. Combined observations support the hypothesis that mesenchymal-epithelial cell interactions between thecal and granulosa cells can play a significant role during ovarian follicular development and mediate gonadotropin actions.     

Effects of retinal laser photocoagulation on photoreceptor basic fibroblast growth factor and survival

PURPOSE: In an unpublished study, the authors found that immunoreactivity for basic fibroblast growth factor (bFGF) is increased in rod photoreceptors adjacent to long-standing laser burns in human diabetic retinas. The goal of this study was to determine whether laser photocoagulation produces a similar increase in photoreceptor bFGF and promotes survival of these cells in dystrophic rodent retinas. METHODS: Threshold (whitening) and subthreshold (nonwhitening) laser burns were made in retinas of normal and Royal College of Surgeons (RCS) rats and normal and rds mice. The retinas were processed for immunocytochemical and morphometric analyses. RESULTS: In nonlasered normal rat and mouse retinas, bFGF immunoreactivity was prominent in the nuclei of Müller cells and astrocytes. Photoreceptors were bFGF negative except for a zone of bFGF-immunoreactive rods near the ora serrata. Some photoreceptors in nonlasered retinas of RCS rats and rds mice became bFGF immunoreactive. After laser treatment, bFGF immunoreactivity was markedly increased in all photoreceptors flanking the threshold burns and within the subthreshold burns in normal and mutant rats and mice. In RCS rat retinas, photoreceptor bFGF immunoreactivity remained elevated within subthreshold burns and flanking the threshold burns, and photoreceptor survival was prolonged. In rds mouse retinas, increased bFGF immunoreactivity in photoreceptors was not sustained and their degeneration was not retarded. CONCLUSIONS: Laser treatment of RCS rat retinas produced a sustained increase in bFGF immunoreactivity in photoreceptors and prolonged their survival, but laser treatment of rds mouse retinas did not have a long-term effect on photoreceptor bFGF immunoreactivity or survival. Although species differences in laser effects on photoreceptor bFGF and survival are apparent, the finding that rods flanking laser burns in human retinas have sustained increases in bFGF immunoreactivity suggests that laser treatment may be useful for prolonging survival of mutant photoreceptors in retinas of patients with retinitis pigmentosa.