Administration Of Platelet-derived Growth Factor Research Articles

PDGF-loaded microneedles promote tendon healing through p38/cyclin D1 pathway mediated angiogenesis.

Tendon injury is one of the most serious orthopedic diseases often leading to disability of patients. Major shortages of tendon healing are due to its multiple comorbidities, uncertainty of therapeutic efficacy and insufficient of angiogenesis. With a deeper understanding of angiogenic mechanism of tendon healing, we investigated an innovative microneedle patch loaded with platelet derived growth factor (PDGF) to achieve a constant systemic administration of PDGF to enhance topical tendon healing. Rat achilles tendon injury model was performed as in vivo animal models. Histological staining showed an enhancement of tendon healing quality, especially angiogenesis. Biomechanical studies demonstrated an increase of tendon stiffness, maximum load and maximum stress with treatment of PDGF-loaded microneedles. Furthermore, MAPK/p38/Cyclin D1 pathway and angiogenesis were found to play an important role in tendon healing process by using a biological high throughput RNA-sequence method and bioinformatic analysis. The high throughput RNA-seq tendon healing results were confirmed by histochemical staining and western blot. These results suggest the novel therapeutic potential of PDGF-loaded microneedle patch in tendon surgery.

Exogenous platelet-derived growth factor improves neurovascular unit recovery after spinal cord injury.

The blood-spinal cord barrier plays a vital role in recovery after spinal cord injury. The neurovascular unit concept emphasizes the relationship between nerves and vessels in the brain, while the effect of the blood-spinal cord barrier on the neurovascular unit is rarely reported in spinal cord injury studies. Mouse models of spinal cord injury were established by heavy object impact and then immediately injected with platelet-derived growth factor (80 μg/kg) at the injury site. Our results showed that after platelet-derived growth factor administration, spinal cord injury, neuronal apoptosis, and blood-spinal cord barrier permeability were reduced, excessive astrocyte proliferation and the autophagy-related apoptosis signaling pathway were inhibited, collagen synthesis was increased, and mouse locomotor function was improved. In vitro, human umbilical vein endothelial cells were established by exposure to 200 μM H2O2. At 2 hours prior to injury, in vitro cell models were treated with 5 ng/mL platelet-derived growth factor. Our results showed that expression of blood-spinal cord barrier-related proteins, including Occludin, Claudin 5, and β-catenin, was significantly decreased and autophagy was significantly reduced. Additionally, the protective effects of platelet-derived growth factor could be reversed by intraperitoneal injection of 80 mg/kg chloroquine, an autophagy inhibitor, for 3 successive days prior to spinal cord injury. Our findings suggest that platelet-derived growth factor can promote endothelial cell repair by regulating autophagy, improve the function of the blood-spinal cord barrier, and promote the recovery of locomotor function post-spinal cord injury. Approval for animal experiments was obtained from the Animal Ethics Committee, Wenzhou Medical University, China (approval No. wydw2018-0043) in July 2018.

The positive impact of platelet-derived growth factor on the repair of full-thickness defects of articular cartilage.

This study aims to investigate the potential use and histological effects of the local administration of platelet-derived growth factor (PDGF) in the repair of full-thickness osteochondral defects in articular cartilage in an animal model. Twenty-four adolescent 18-week-old New Zealand White rabbits with an average weight of 2500 g (range, 1600 g to 3200 g) were used in the study. The rabbits were randomly divided into three groups (n=8) as the control group (group A) and two experimental groups (groups B and C). Defects of cylindrical full-thickness (3.5 mm wide, 4 mm deep) were created in the weight-bearing area of the right knee medial femoral condyles. In group A, the defect was left empty. In group B, the defect was filled with a collagen sponge. In group C, the defect was filled with a collagen sponge impregnated with PDGF. All rabbits were followed-up for 12 weeks. Right knee medial femoral condyles were used for macroscopic and histological analyses. At macroscopic level, the repair tissue was similar to normal adjacent cartilage at 12 weeks in group C. The surface of the repair tissue in group C was smoother and more regular compared to groups A and B. The total histological score of defects in group C was statistically significantly superior compared to groups A and B (p<0.05). Matrix staining and immunostaining of collagen type 2 were stronger in group C compared to the other groups, indicating the presence of a tissue similar to a normal cartilage. Platelet-derived growth factor can induce repair in full-thickness defects of articular cartilage in an animal model. Thus, this study demonstrates the potential use of PDGF for full-thickness osteochondral defects.

Local administration of platelet-derived growth factor B (PDGFB) improves follicular development and ovarian angiogenesis in a rat model of Polycystic Ovary Syndrome

Alterations in ovarian angiogenesis are common features in Polycystic Ovary Syndrome (PCOS) patients; the most studied of these alterations is the increase in vascular endothelial growth factor (VEGF) production by ovarian cells. Platelet-derived growth factor B (PDGFB) and D (PDGFD) are decreased in follicular fluid of PCOS patients and in the ovaries of a rat model of PCOS. In the present study, we aimed to analyze the effects of local administration of PDGFB on ovarian angiogenesis, follicular development and ovulation in a DHEA-induced PCOS rat model. Ovarian PDGFB administration to PCOS rats partially restored follicular development, decreased the percentage of cysts, increased the percentage of corpora lutea, and decreased the production of anti-Müllerian hormone. In addition, PDGFB administration improved ovarian angiogenesis by reversing the increase in periendothelial cell area and restoring VEGF levels. Our results shed light into the mechanisms that lead to altered ovarian function in PCOS and provide new data for potential therapeutic strategies.

Effect of local administration of platelet-derived growth factor B on functional recovery of peripheral nerve regeneration: A sciatic nerve transection model.

Effects of platelet-derived growth factor B (PDGF-B) on peripheral nerve regeneration was studied using a rat sciatic nerve transection model. Forty-five male, white Wistar rats were divided into three experimental groups (n = 15), randomly: Normal control group (NC), silicon group (SIL), and PDGF-B treated group (SIL/PDGF). In NC group, left sciatic nerve was exposed through a gluteal muscle incision and after homeostasis muscle was sutured. In the SIL group, the left sciatic nerve was exposed in the same way and transected proximal to tibio-peroneal bifurcation leaving a 10-mm gap. Proximal and distal stumps were each inserted into a silicone conduit and filled with 10 μL phosphate buffered solution. In SIL/PDGF group, the silicon conduit was filled with 10 μL PDGF-B (0.5 ng/mL). Each group was subdivided into three subgroups of five and were studied in 4, 8, 12 weeks after surgery. Behavioral testing, sciatic nerve functional study, gastrocnemius muscle mass, and histomorphometric studies showed earlier regeneration of axons in SIL/PDGF than in SIL group (P < 0.05). Local administration of PDGF-B combined with silicon grafting could accelerate functional recovery and may have clinical implications for the surgical management of patients after facial nerve transection.

Platelet-Derived Growth Factor in Heart Failure.

Defective vascular and cardiomyocyte function are implicated in the development and progression of both heart failure with reduced and preserved ejection fraction. Any treatment option that augments these myocardial processes may therefore be of significant value. The platelet-derived growth factor (PDGF) family is involved in a wide range of growth processes and plays a key role in both regulating angiogenesis and mesenchymal cell development. Thus, PDGF may serve as a potent therapy for heart failure. While numerous animal studies have demonstrated beneficial cardiovascular effects of growth factor therapy, promising laboratory data has not yet translated to effective therapies. In this review, we outline the biological role of PDGF and summarize previous studies that have focused on the cardiovascular effects of normal PDGF signaling, administration of PDGF, and the effects of PDGF on stem cell therapy.

PDGF supplementation alters oxidative events in wound healing process: a time course study

Platelet-derived growth factor (PDGF), an important stimulant, plays a role in almost all stages of wound healing process. In various studies, it has been shown that PDGF has healing effects in this process. In the present study, we especially focused on investigating the effects of exogenous PDGF administration on oxidative events during cutaneous wound healing process. Experiments were performed on 42 female Wistar-albino rats. Animals were divided into four groups: control, untreated, chitosan-treated and chitosan + PDGF-treated. Two uniform full-thickness excisional skin wounds were made under anesthesia in all animals except control group. In the chitosan + PDGF-treated groups, the wounds were treated topically with a single daily dose PDGF-BB (7 ng/ml) after wounding. In the chitosan-treated groups, the wounds were treated topically with equal amount of blank chitosan gel. After that, on the 3rd and 7th days of wound healing, the animals were killed. Thiobarbituric acid-reactive substances (TBARS), nitric oxide (NOx), ascorbic acid (AA), glutathione (GSH) levels and superoxide dismutase (SOD) activity were measured spectrophotometrically in the wound tissues. PDGF significantly increased TBARS levels in early phase of wound healing. In contrast, it significantly decreased TBARS levels in later phase of healing. In the chitosan + PDGF-treated group, NOx levels decreased on days 3 and 7 when compared with the chitosan-treated groups. Non-enzymatic antioxidant levels were increased by PDGF administration and this may have contributed to increase in wound tissue antioxidant capacity. In the light of these findings, PDGF supplementation may have altering effects on oxidative events depending on the time in wound healing process.

Regulation of arterial blood pressure by Akt1-dependent vascular relaxation

Endothelial cell-dependent vascular relaxation plays an important role in the regulation of blood pressure. Here, we show that stimulation of vascular endothelial cells with platelet-derived growth factor (PDGF) results in vascular relaxation through Akt1-dependent activation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) production. Stimulation of both human umbilical artery endothelial cells and abdominal aortic vessels with PDGF induced NO production. PDGF-dependent production of NO was completely abolished by inhibition of phosphatidylinositol 3-kinase with wortmannin (100nM). Stimulation of aortic vessels with PDGF resulted in the activation of Akt phosphorylation and eNOS phosphorylation: however, eNOS phosphorylation and production of NO were abolished in aortic vessels of mice lacking Akt1. PDGF strongly induced vascular relaxation in the presence of endothelium, and inhibition of NO production by N-nitro-L: -arginine-methyl ester completely blocked PDGF-dependent vascular relaxation. In addition, PDGF-dependent relaxation was completely abolished by inhibition of PI3K with wortmannin (100nM). Furthermore, vessels from Akt1 heterozygotes showed normal relaxation after PDGF stimulation, whereas vessels from Akt1 knockout littermates did not respond to PDGF stimulation. Finally, administration of PDGF (5ng/ml) significantly lowered blood pressure in Akt1 heterozygotes, whereas a blood pressure-lowering effect was not observed in Akt1 knockout littermates. These results suggest that Akt1 regulates blood pressure through regulation of vascular relaxation by eNOS phosphorylation and subsequent production of NO.

Intrathecal Delivery of PDGF Produces Tactile Allodynia through its Receptors in Spinal Microglia

Neuropathic pain is a debilitating pain condition that occurs after nerve damage. Such pain is considered to be a reflection of the aberrant excitability of dorsal horn neurons. Emerging lines of evidence indicate that spinal microglia play a crucial role in neuronal excitability and the pathogenesis of neuropathic pain, but the mechanisms underlying neuron-microglia communications in the dorsal horn remain to be fully elucidated. A recent study has demonstrated that platelet-derived growth factor (PDGF) expressed in dorsal horn neurons contributes to neuropathic pain after nerve injury, yet how PDGF produces pain hypersensitivity remains unknown. Here we report an involvement of spinal microglia in PDGF-induced tactile allodynia. A single intrathecal delivery of PDGF B-chain homodimer (PDGF-BB) to naive rats produced a robust and long-lasting decrease in paw withdrawal threshold in a dose-dependent manner. Following PDGF administration, the immunofluorescence for phosphorylated PDGF β-receptor (p-PDGFRβ), an activated form, was markedly increased in the spinal dorsal horn. Interestingly, almost all p-PDGFRβ-positive cells were double-labeled with an antibody for the microglia marker OX-42, but not with antibodies for other markers of neurons, astrocytes and oligodendrocytes. PDGF-stimulated microglia in vivo transformed into a modest activated state in terms of their cell number and morphology. Furthermore, PDGF-BB-induced tactile allodynia was prevented by a daily intrathecal administration of minocycline, which is known to inhibit microglia activation. Moreover, in rats with an injury to the fifth lumbar spinal nerve (an animal model of neuropathic pain), the immunofluorescence for p-PDGFRβ was markedly enhanced exclusively in microglia in the ipsilateral dorsal horn. Together, our findings suggest that spinal microglia critically contribute to PDGF-induced tactile allodynia, and it is also assumed that microglial PDGF signaling may have a role in the pathogenesis of neuropathic pain.

The Early Effects of Sustained Platelet-Derived Growth Factor Administration on the Functional and Structural Properties of Repaired Intrasynovial Flexor Tendons: An In Vivo Biomechanic Study at 3 Weeks in Canines

A bioactive fibrin-based delivery system was used to provide sustained administration of platelet-derived growth factor (PDGF-BB) in a clinically relevant model of intrasynovial flexor tendon repair. We hypothesized that PDGF-BB administered in this manner would improve the sutured tendon's functional and structural properties 3 weeks after repair. A delivery system consisting of 30 microL of fibrin matrix, peptide, heparin, and 100 ng of PDGF-BB was incorporated into the repair sites of randomly selected medial or lateral forepaw flexor digitorum profundus tendons of 8 adult mongrel dogs. The remaining forepaw flexor digitorum profundus tendons were repaired without the growth-factor and fibrin-based delivery system and served as controls. The surgically treated forelimbs were treated with controlled passive motion rehabilitation. The animals were killed at 3 weeks, at which time the tendons were tested for range of motion with a motion analysis system and for tensile properties with a materials testing machine. Proximal interphalangeal joint and distal interphalangeal joint rotation values were significantly higher for the PDGF-BB-treated tendons compared with the repair-alone tendons. Excursion values were also significantly higher in the PDGF-BB-treated tendons. There were no significant differences in tensile properties when comparing PDGF-BB-treated with repair-alone tendons. The functional properties of repaired intrasynovial flexor tendons were significantly improved with the sustained administration of PDGF-BB. The failure to achieve improvements in ultimate load, stiffness, and strain in the experimental group may have been due to suboptimal PDGF-BB dosage or suboptimal release kinetics.

Acceleration of Normal-Tissue Damage Expression by Early Stimulation of Cell Proliferation in Rat Spinal Cord

To examine experimental strategies for prevention of radiation-induced late spinal cord damage. The effects of treatment with high, proliferation-stimulating doses of platelet-derived growth factor (PDGF) administered at various times after radiotherapy of rat spinal cord, and aiming at increased tissue regeneration, were studied in an established model. Animals were followed and monitored for expression of radiation myelopathy (RM), which was confirmed by histopathologic diagnosis. High doses of PDGF given 8 weeks after radiotherapy significantly accelerated the development of RM compared to control animals (Figure 1). Such effects were observed also for concomitant treatment, but not for PDGF administration after 12 or 15 weeks (Figure 2). On the microscopic level, the spinal cord showed more pronounced vascular damage with vessel necroses and hemorrhages (Figure 3). These data suggest that the vascular system plays an important role during development of RM and that early stimulation of cell proliferation negatively influences the time course of spinal cord damage. Further experiments should address different concepts of tissue regeneration or damage prevention.

Hepatocyte Growth Factor/Scatter Factor and MET Are Involved in Arterial Repair and Atherogenesis

Several studies have shown that in the arterial wall hepatocyte growth factor/scatter factor (HGF/SF) is expressed by smooth muscle cells (SMCs) but acts on endothelial cells, not SMCs. Other studies, however, have indicated that SMCs can respond to HGF/SF. We have reinvestigated expression and activity of HGF/SF and its receptor MET in arterial SMC and endothelial cell cultures and in whole arteries after superficial or deep injury or atherogenesis. High-density cultures of SMCs produced HGF/SF but did not express MET, whereas SMCs, at the leading edge of injured cultures, expressed both ligand and receptor and showed a dramatic motility and growth response to HGF/SF. In line with these results, HGF/SF and MET expression was undetectable in the media of uninjured carotid arteries but was induced after deep arterial injury in areas of SMC migration in the neointima. Strong MET expression was also observed in the SMCs of the atherosclerotic lesions of homozygous apoE(-/-) mice, whereas HGF/SF was expressed by macrophage-derived foam cells. These results demonstrate that MET is induced in migrating and proliferating SMCs and that HGF/SF and MET are key mediators of the SMC response in atherogenesis.

Modulation of rodent spinal cord radiation tolerance by administration of platelet-derived growth factor

To examine the role of platelet-derived growth factor (PDGF) for ameliorating radiation myelopathy of the cervical spinal cord in a rodent model. After developing the technique for cannulation of the basal cistern, initial animal experiments were conducted to test the feasibility of intrathecal continuous infusion of PDGF in a model of cervical spinal cord irradiation in adult Fisher F-344 rats and to determine the most effective dose level of PDGF. Subsequently, the dose-modification factor was determined in a larger group of rats. Irradiation was given in 2 fractions (16 Gy followed by 14-24 Gy) and animals were examined for the development of paresis. The initial dose-finding experiment revealed significant differences in the incidence of radiation myelopathy (100% in saline-treated control rats, 25% with the most effective dose of PDGF, up to 100% with less effective doses). The most effective dose of PDGF was 0.014 mug per day. Subsequent experiments revealed a median effective dose (ED(50)) of 35.6 Gy (95% confidence interval, 34.7-36.5 Gy) for animals receiving this dose of PDGF in contrast to 33.8 Gy (33.4-34.3 Gy) for the control group (p = 0.003). The dose-modification factor obtained with this dose of PDGF was 1.05. Intrathecal administration of PDGF concomitant to irradiation of the cervical spinal cord in rats was feasible. Treatment with PDGF significantly increased the tolerance of the spinal cord. The PDGF experiments should be viewed as a proof of principle that brief therapeutic intervention in the earliest phase of damage induction can reduce late effects in the spinal cord. They form the basis for further studies of growth factor administration in this particular model.

Effect of exogenous administration of platelet-derived growth factor and epidermal growth factor on duodenal ulcer healing in rats treated with indomethacin

Nonsteroidal anti-inflammatory drugs (NSAIDs) delay peptic ulcer healing through mechanisms that are still not entirely understood. Growth factors play a significant role in healing. To evaluate whether exogenous administration of platelet-derived growth factor (PDGF) reverses the effect of indomethacin in experimental duodenal ulcers in rats and to define the potential mechanisms involved in this process. Duodenal ulcer was induced in male Wistar rats with acetic acid. The rats were then administered indomethacin (2 mg/kg/day), PDGF-BB (30 ng/100 g/day), epidermal growth factor (EGF) (50 /kg/day) or famotidine (positive control) or the possible combinations of these. Macroscopic area, reduction in microscopic diameter, epithelial and granulation tissue proliferation, collagen secretion by granulation tissue, and gastric acid secretion were analyzed. Indomethacin delayed duodenal ulcer healing by decreasing cellular proliferation and inhibiting collagen secretion. PDGF and EGF accelerated healing and reversed the effects of indomethacin. The mechanisms involved were associated with an increase in collagen proliferation and secretion without affecting gastric acid secretion. Famotidine also accelerated healing and reversed the effect of indomethacin, and these effects were associated with a marked inhibition of gastric acid secretion and increase in collagen secretion by granulation tissue. Exogenous administration of PDGF and EGF accelerated healing and reversed the harmful effects of indomethacin in an experimental model of duodenal ulcer.

Augmentation of kidney injury by basic fibroblast growth factor or platelet-derived growth factor does not induce progressive diabetic nephropathy in the Goto Kakizaki model of non-insulin-dependent diabetes

Diabetes is now the most common cause of kidney failure. The pathogenesis of diabetic nephropathy in both type 1 and type 2 diabetes, however, is still incompletely understood. Two mechanisms postulated to contribute to the pathogenesis of progressive diabetic nephropathy are glomerular cell proliferation and glomerular visceral epithelial cell or podocyte injury. The aim of the current study was to determine whether the aggravation of mesangial cell injury or podocyte injury in isolation would induce progressive diabetic nephropathy. Specifically, we examined whether the administration of either platelet-derived growth factor (PDGF) or basic fibroblast growth factor (bFGF) in sub-nephritogenic doses might lead to an aggravation of kidney structural changes associated with hyperglycemia, resulting in progressive kidney damage in the Goto Kakizaki (GK) rat, which is a genetic model of non-obese non-insulin-dependent diabetes mellitus (NIDDM), in which progressive kidney disease does not develop spontaneously. The results demonstrate that the administration of PDGF to hyperglycemic GK rats led to acute mesangial cell proliferation and activation as assessed by 5-bromo-2′-deoxyuridine-positive nuclei and immunostaining for α-smooth muscle actin. Despite acute mesangial cell activation and proliferation, PDGF treatment had no long-term effect on either kidney structure or function. Similarly, treatment of GK rats with bFGF, despite the augmentation of podocyte injury as demonstrated by de novo expression of glomerular desmin expression, did not lead to the development of progressive diabetic nephropathy. In summary, the data in the current manuscript suggest that the additive effect of hyperglycemia and superimposed isolated mesangial cell or podocyte injury does not lead to progressive diabetic nephropathy. This further emphasises the multifactorial nature of the pathogenesis of progressive diabetic nephropathy.

Effect of combined administration of insulin-like growth factor and platelet-derived growth factor on the regeneration of transected and anastomosed sciatic nerve in rats

Abstract Objective To evaluate the efficacy of combined administration of platelet-derived growth factor (PDGF) and insulin-like growth factor (IGF-I) on the regeneration of transected and anastomosed sciatic nerves. Animals 25 male Lewis rats. Procedure Transection and anastomosis was performed of the left sciatic nerve of all rats. At the time of surgery, treatment group rats received a combination of PDGF (0.75 μg) and IGF-I (1.5 μg) along with vehicle (2% methyl cellulose gel) at the anastomosis site. Control rats received vehicle alone. Evaluation consisted of motor evoked potentials and nerve conduction velocity, quantitative histologic examination, sciatic functional index, and visual assessment of repair organization (lesion scores). Results Significant differences in motor evoked potential latency, nerve conduction velocity, axon number, sciatic functional index, or lesion scores were not found between groups. Conclusions Combined administration of PDGF and IGF-I did not enhance peripheral nerve regeneration in a transection and anastomosis model as determined 6 weeks after surgery. Clinical Relevance These findings support the assumption that mechanical, versus trophic, effects predominate when nerve ends are closely apposed. (Am J Vet Res 1997;58:1033–1037)

The effect of systemically administered PDGF-BB on the rodent skeleton.

Platelet-derived growth factor (PDGF), an osteoblast mitogen, has been demonstrated to accelerate fracture healing and periodontal bone repair when applied locally in vivo. To explore whether PDGF could stimulate bone formation in intact bone, we administered it systemically to rats rendered acutely estrogen-deficient. Because PDGF may stimulate bone resorption in vitro, PDGF was administered with and without an antiresorptive agent (alendronate). All treatments were given by intravenous injection 3 times a week for 6 weeks. Spinal bone mineral density (BMD) decreased by 5% in the vehicle-treated ovariectomized (OVX) rats by the end of the study as determined by DXA. Treatment with PDGF prevented this bone loss and significantly (p < 0.05) increased the bone density in the spine (9%) and whole skeleton (5.8%). Combined treatment with PDGF and alendronate resulted in a greater increase at the spine (18%) and whole skeleton (12.8%) than either agent alone. Histomorphometric analysis demonstrated that treatment with PDGF increased the osteoblast number and osteoblast perimeter without consistent changes in osteoclast estimates. Biomechanical testing demonstrated that PDGF administration increased the vertebral body compressive strength and femoral shaft torsional stiffness and resulted in a trend for enhanced femoral head shearing strength. Coadministration of alendronate further increased these indices of bone strength. PDGF administration also caused premature closure of the growth plate, decreased body fat, and resulted in extraskeletal collagen deposition. We therefore demonstrate, for the first time, that systemic administration of PDGF can increase bone density and strength throughout the skeleton.

The effect of PDGF on the healing of full thickness wounds in hairless guinea pigs

1. 1. Platelet-derived growth factor (PDGF), administered daily for 5 days and every other day for 9 additional days or the day of wounding and the following day, caused dose dependent (0.2, 1.0 or 5.0 μg PDGF/wound) increased granulation tissue. 2. 2. The two day 5.0 μg treatment resulted in a 73% increase and the multi-day treatment resulted in a 52% increase of alkaline phosphatase activity three days after wounding. 3. 3. Multi-day treatment resulted in significant increases in protein synthesis (132%), vimentin content (160%) and excised wound weight (76%) three days after wounding. 4. 4. These results indicate that limited administration of PDGF alters wound healing although multiple applications provoke a more dramatic response.

Early metabolic effects of platelet-derived growth factor and transforming growth factor-beta in rat liver in vivo.

The short term metabolic effects of the in vivo administration of platelet-derived growth factor have been examined in the liver of the rat. Meal-fed male Wistar rats weighing between 150-180 g received an intraperitoneal injection of platelet-derived growth factor (17 units/100 g weight), transforming growth factor-beta (185 ng/100 g weight), or saline. At 5 min after injection, the livers were freeze-clamped. Samples of the tissue were subsequently assayed for metabolite content and enzyme activities. Platelet-derived growth factor injection caused an elevation in the liver content of pyruvate from 0.14 +/- 0.012 to 0.19 +/- 0.009 mumol/g wet weight liver (p less than or equal to 0.01) and an increase in the cytosolic phosphorylation potential [sigma ATP]/[sigma ADP][sigma Pi] from 6670 +/- 540 to 8970 +/- 750 (p less than or equal to 0.01). In addition an increase in the hepatic content of the hexose monophosphate pathway metabolites, 6-phosphogluconate (0.027 +/- 0.004 to 0.037 +/- 0.005 mumol/g wet weight) (p less than or equal to 0.05), ribulose 5-phosphate (0.013 +/- 0.001 to 0.017 +/- 0.001 mumol/g wet weight) (p less than or equal to 0.05) and combined sedoheptulose 7-phosphate and ribose 5-phosphate (0.052 +/- 0.007 to 0.062 +/- 0.004 mumol/g wet weight) (p less than or equal to 0.05) was observed. The elevation in the hexose monophosphate pathway metabolites resulted from a 1.3-fold elevation in the activity of glucose-6-phosphate dehydrogenase [EC 1.1.1.49] when measured in a crude homogenate. Kinetic analysis performed on partially purified glucose-6-phosphate dehydrogenase demonstrated no significant change in the Km of the enzyme for either NADP+ or glucose 6-phosphate, while a 2.4-fold increase in the Vmax was observed. In view of the rapidity of the change in total measured enzyme activity and increase in the Vmax of glucose-6-phosphate dehydrogenase, it is postulated that platelet-derived growth factor causes a covalent modification of the existing enzyme. Transforming growth factor-beta caused no change in the hepatic metabolite content in the treated animals when compared to saline treated controls.