Overexpression Of Platelet-derived Growth Factor Research Articles

Development of a Chimeric Protein BiPPB-mIFNγ-tTβRII for Improving the Anti-Fibrotic Activity in Vivo by Targeting Fibrotic Liver and Dual Inhibiting the TGF-β1/Smad Signaling Pathway.

Excessive production of transforming growth factor β1 (TGF-β1) in activated hepatic stellate cells (aHSCs) promotes liver fibrosis by activating the TGF-β1/Smad signaling pathway. Thus, specifically inhibiting the pro-fibrotic activity of TGF-β1 in aHSCs is an ideal strategy for treating liver fibrosis. Overexpression of platelet-derived growth factor β receptor (PDGFβR) has been demonstrated on the surface of aHSCs relative to normal cells in liver fibrosis. Interferon-gamma peptidomimetic (mIFNγ) and truncated TGF-β receptor type II (tTβRII) inhibit the TGF-β1/Smad signaling pathway by different mechanisms. In this study, we designed a chimeric protein by the conjugation of (1) mIFNγ and tTβRII coupled via plasma protease-cleavable linker sequences (FNPKTP) to (2) PDGFβR-recognizing peptide (BiPPB), namely BiPPB-mIFNγ-tTβRII. This novel protein BiPPB-mIFNγ-tTβRII was effectively prepared using Escherichia coli expression system. The active components BiPPB-mIFNγ and tTβRII were slowly released from BiPPB-mIFNγ-tTβRII by hydrolysis using the plasma protease thrombin in vitro. Moreover, BiPPB-mIFNγ-tTβRII highly targeted to fibrotic liver tissues, markedly ameliorated liver morphology and fibrotic responses in chronic liver fibrosis mice by both inhibiting the phosphorylation of Smad2/3 and inducing the expression of Smad7. Meanwhile, BiPPB-mIFNγ-tTβRII markedly reduced the deposition of collagen fibrils and expression of fibrosis-related proteins in acute liver fibrosis mice. Furthermore, BiPPB-mIFNγ-tTβRII showed a good safety performance in both liver fibrosis mice. Taken together, BiPPB-mIFNγ-tTβRII improved the in vivo anti-liver fibrotic activity due to its high fibrotic liver-targeting potential and the dual inhibition of the TGF-β1/Smad signaling pathway, which may be a potential candidate for targeting therapy on liver fibrosis.

Overexpression of Platelet-Derived Growth Factor and Its Receptor Are Correlated with Oral Tumorigenesis and Poor Prognosis in Oral Squamous Cell Carcinoma.

Oral squamous cell carcinoma (OSCC) is a cancerous disease with poor prognosis. According to the statistics, the 5-year survival rate has not improved significantly over the past 20 years. The platelet-derived growth factor (PDGF) and its signaling pathway is a key regulator of angiogenesis and tumorigenesis. High level of PDGF and its receptor (PDGFR) have been reported in several types of malignancies. In this study, we investigated the relationship of the molecular expression levels of PDGF and PDGFR with clinicopathological parameters in OSCC. To this end, we measured the mRNA and protein levels of PDGF and PDGFR by real-time quantitative PCR (qRT-PCR), immunohistochemistry, and enzyme-linked immunosorbent assay (ELISA), respectively. We found positive correlations of the mRNA levels of PDGFA, PDGFB, and PDGFRB with lymph node metastasis and poor overall survival (OS). High expression of PDGF, PDGFRA, and PDGFRB were remarkably associated with lymph node metastasis and poor OS, as determined by immunohistochemistry. Preoperative serum levels of PDGF-AA and PDGF-BB had a positive correlation with preoperative platelet count. Elevated serum levels of PDGF-AA. PDGF-BB, and platelet count correlated with lymph node metastasis and an unfavorable outcome. In multivariate Cox regression analysis, PDGFA mRNA, PDGFB mRNA, PDGFRB mRNA, PDGF immunoexpression, PDGFRB immunoexpression, serum PDGF-AA, serum PDGF-BB, and platelet count emerged as significant independent prognostic factors for OS. In vitro, we found that elevated PDGF promotes colony formation, migration, and invasiveness of SAS and OECM-1 cancer cell lines. Our results suggest that the expression level of serum PDGF has the potential to become a useful diagnostic marker for the prognosis of OSCC. In addition, PDGFR should be considered as a potential therapeutic target for OSCC. Furthermore, research should be undertaken to elucidate the role of PDGF and PDGFR regarding the behavior of tumor cells in OSCC.

Combinatorial lentiviral gene delivery of pro-oligodendrogenic factors forimprovingmyelination of regenerating axons after spinal cord injury.

Spinal cord injury (SCI) results in paralysis below the injury and strategies are being developed that support axonal regrowth, yet recovery lags, in part, because many axons are not remyelinated. Herein, we investigated strategies to increase myelination of regenerating axons by overexpression of platelet-derived growth factor (PDGF)-AA and noggin either alone or in combination in a mouse SCI model. Noggin and PDGF-AA have been identified as factors that enhance recruitment and differentiation of endogenous progenitors to promote myelination. Lentivirus encoding for these factors was delivered from a multichannel bridge, which we have previously shown creates a permissive environment and supports robust axonal growth through channels. The combination of noggin+PDGF enhanced total myelination of regenerating axons relative to either factor alone, and importantly, enhanced functional recovery relative to the control condition. The increase in myelination was consistent with an increase in oligodendrocyte-derived myelin, which was also associated with a greater density of cells of an oligodendroglial lineage relative to each factor individually and control conditions. These results suggest enhanced myelination of regenerating axons by noggin+PDGF that act on oligodendrocyte-lineage cells post-SCI, which ultimately led to improved functional outcomes.

Quantitative Proteomics of TRAMP Mice Combined with Bioinformatics Analysis Reveals That PDGF-B Regulatory Network Plays a Key Role in Prostate Cancer Progression.

Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice is a widely used transgenic animal model of prostate cancer (PCa). We performed a label-free quantitative proteomics analysis combined with a bioinformatics analysis on the entire prostate protein extraction from TRAMP mice and compared it with WT littermates. From 2379 total identified proteins, we presented a modest mice prostate reference proteome containing 919 proteins. 61 proteins presented a significant expression difference between two groups. The integrative bioinformatics analysis predicted the overexpression of platelet-derived growth factor B (PDGF-B) in tumor tissues and supports the hypothesis of the PDGF-B signaling network as a key upstream regulator in PCa progression. Furthermore, we demonstrated that Crenolanib, a novel PDGF receptor inhibitor, inhibited PCa cell proliferation in a dose-dependent manner. Finally, we revealed the importance of PDGF-B regulatory network in PCa progression, which will assist us in understanding the role and mechanisms of PDGF-B in promoting cancer growth and provide valuable knowledge for future research on anti-PDGF therapy.

Homocysteine Facilitates Prominent Polygonal Angiogenetic Networks of a Choroidal Capillary Sprouting Model.

To investigate the effects of homocysteine on choroidal angiogenesis, we established an ex vivo choroidal sprouting explant model and examined the potential growth factors for angiogenesis. Choroid fragments with retinal pigment epithelium were isolated from mouse and embedded in Matrigel. Homocysteine at different concentrations were added to the culture mediums. The choroidal explants were observed at different time points, and the total area of choroidal sprouting was measured and analyzed. Homocysteine evoked choroidal capillary sprouting by inducing capillary endothelial cell proliferation with pericyte formation and by facilitating polygonal angiogenetic networks. In some cases, vascular lumens were observed in the newly forming capillaries facilitated by homocysteine. The choroidal sprouting effect of homocysteine can only be observed at a certain range of homocysteine concentration, with 1-mM homocysteine exhibiting the most significantly increased choroidal sprouting areas. Isolectin overexpression was noted in the homocysteine-treated group. Possible growth factors for angiogenesis were detected through immunofluorescent staining, which demonstrated the overexpression of platelet-derived growth factor C and angiopoietin 1 in the homocysteine-treated preparations only. In these preparations, platelet-derived growth factor C was highly expressed in the tip cells of sprouting capillaries. We therefore conclude that platelet-derived growth factor C and angiopoietin 1 may play key roles in the choroid angiogenesis evoked by homocysteine.

Simulating PDGF-Driven Glioma Growth and Invasion in an Anatomically Accurate Brain Domain.

Gliomas are the most common of all primary brain tumors. They are characterized by their diffuse infiltration of the brain tissue and are uniformly fatal, with glioblastoma being the most aggressive form of the disease. In recent years, the over-expression of platelet-derived growth factor (PDGF) has been shown to produce tumors in experimental rodent models that closely resemble this human disease, specifically the proneural subtype of glioblastoma. We have previously modeled this system, focusing on the key attribute of these experimental tumors-the "recruitment" of oligodendroglial progenitor cells (OPCs) to participate in tumor formation by PDGF-expressing retrovirally transduced cells-in one dimension, with spherical symmetry. However, it has been observed that these recruitable progenitor cells are not uniformly distributed throughout the brainand that tumor cells migrate at different rates depending on the material properties in different regions of the brain. Here we model the differential diffusion of PDGF-expressing and recruited cell populations via a system of partial differential equations with spatially variable diffusion coefficients and solve the equations in two spatial dimensions on a mouse brain atlas using a flux-differencing numerical approach. Simulations of our in silico model demonstrate qualitative agreement with the observed tumor distribution in the experimental animal system. Additionally, we show that while there are higher concentrations of OPCs in white matter, the level of recruitment of these plays little role in the appearance of "white matter disease," where the tumor shows a preponderance for white matter. Instead, simulations show that this is largely driven by the ratio of the diffusion rate in white matter as compared to gray. However, this ratio has less effect on the speed of tumor growth than does the degree of OPC recruitment in the tumor. It was observed that tumor simulations with greater degrees of recruitment grow faster and develop more nodular tumors than if there is no recruitment at all, similar to our prior results from implementing our model in one dimension.Combined, these results show that recruitment remains an important consideration in understanding and slowing glioma growth.

Platelet-Derived Growth Factor Over-Expression in Retinal Progenitors Results in Abnormal Retinal Vessel Formation

Platelet-derived growth factor (PDGF) plays an important role in development of the central nervous system, including the retina. Excessive PDGF signaling is associated with proliferative retinal disorders. We reported previously that transgenic mice in which PDGF-B was over-expressed under control of the nestin enhancer, nes/tk-PdgfB-lacZ, exhibited enhanced apoptosis in the developing corpus striatum. These animals display enlarged lateral ventricles after birth as well as behavioral aberrations as adults. Here, we report that in contrast to the relatively mild central nervous system phenotype, development of the retina is severely disturbed in nes/tk-PdgfB-lacZ mice. In transgenic retinas all nuclear layers were disorganized and photoreceptor segments failed to develop properly. Since astrocyte precursor cells did not populate the retina, retinal vascular progenitors could not form a network of vessels. With time, randomly distributed vessels resembling capillaries formed, but there were no large trunk vessels and the intraocular pressure was reduced. In addition, we observed a delayed regression of the hyaloid vasculature. The prolonged presence of this structure may contribute to the other abnormalities observed in the retina, including the defective lamination.

Urinary Platelet-Derived Growth Factor-BB as an Early Marker of Nephropathy in Patients with Type 2 Diabetes: An Egyptian Study

Background: Diabetic nephropathy (DN) is one of the most serious complications of diabetes worldwide. Strong evidence suggests that several growth factors may contribute to the initiation and progressive fibrosis of DN. Recently, there is an overexpression of platelet-derived growth factor (PDGF) in renal biopsies from patients with DN. This study aimed to investigate the clinical significance of urinary PDGF-BB level in type 2 diabetic patients with and without nephropathy and to evaluate its relationship with various clinical and laboratory parameters. Methods: Urinary levels of PDGF-BB were measured in 60 Egyptian type 2 diabetic patients categorized into three equal groups (normo-, micro-, and macroalbuminuria), according to urinary albumin level. In addition, 20 healthy subjects were selected to serve as controls. Results: The urinary PDGF-BB levels were significantly increased in type 2 diabetic patients as compared to controls (p < 0.001). Moreover, diabetics with micro- and macroalbuminuria had significantly higher levels than in those with normoalbuminuria (p < 0.001). Urinary PDGF-BB correlated positively with disease duration, low-density lipoprotein (LDL)-cholesterol, and urinary albumin and negatively with creatinine clearance in diabetic patients. In a multiple regression model, urinary PDGF-BB was strongly and independently associated with nephropathy in diabetic patients (β = −0.03, p < 0.001). Conclusions: PDGF-BB may play an important role in the initiation and progression of DN. It is considered as a good predictor for early deterioration of renal function in DN. Thus, measurement of urinary PDGF-BB in type 2 diabetic patients could be used for early detection of diabetic renal disease.

Platelet-Derived Growth Factor Regulates Breast Cancer Progression via β-Catenin Expression

Objective: The knowledge on the association between platelet-derived growth factor (PDGF) signaling and epithelial cancers is scarce, although overexpression of PDGF and PDGF receptors has been reported in some human mesenchymal tumors. Thus, we studied the effect of PDGF on breast cancer cells in vitro and the distribution of PDGF in breast cancer tissues. Methods: The effect of PDGF-BB on breast cancer cells was assessed by Western blotting, immunofluorescence, WST and 5-bromo-2-deoxyuridine incorporation experiments. PDGF-B and β-catenin expression was investigated in breast cancer tissues by immunohistochemistry. Results: PDGF-BB induces β-catenin expression in breast cancer cells, and immunohistochemically the distribution of PDGF-B was similar to β-catenin in breast cancer cells. PDGF-B-positive cancer cells were more frequent in cases of ductal carcinoma in situ (87.5%) than invasive carcinoma (61.2%). In addition, PDGF-B staining was stronger in intraductal than invasive cancer cells. PDGF-BB tended to induce nuclear translocation of β-catenin, cell proliferation and DNA incorporation in MDA-MB231 cells, while these results were not found in MCF-7 cells. Conclusion: Our results suggest that PDGF-BB regulates protein expression of β-catenin and is associated with cancer cell behavior.

Retroviral Delivery of Platelet-Derived Growth Factor to Spinal Cord Progenitor Cells Drives the Formation of Intramedullary Gliomas

High-grade gliomas of the spinal cord are poorly understood tumors that are very commonly associated with bad outcomes. The transforming effects of platelet-derived growth factor (PDGF) on spinal cord glial progenitor cells may play an important role in the development of these tumors. To investigate the possible tumor-initiating effects of PDGF overexpression in the spinal cord, we delivered a PDGF retrovirus directly into the substance of the spinal cord. The spinal cords of wild-type adult rats were surgically exposed and injected with 10⁶ colony-forming units of a green fluorescent protein-tagged, PDGF-expressing retrovirus. A control virus was injected to assess the cell types that become infected during retroviral delivery to the spinal cord. It was observed that PDGF overexpression in the spinal cord causes morbidity from high-grade intramedullary glioma formation between 27 and 49 days after PDGF retrovirus injection. Retroviral transduction was highly efficient with 100% of injected animals displaying the tumor phenotype. The tumors produced were highly proliferative, were locally invasive, and displayed the immunophenotype of virus-targeted glial progenitor cells (Olig2+PDGFR+NG2+GFAP-). PDGF is capable of driving glial progenitor cells within the adult spinal cord to form high-grade gliomas. Further investigation of PDGF signaling in the spinal cord is needed to better understand and treat these devastating tumors.

Enlarged lateral ventricles and aberrant behavior in mice overexpressing PDGF-B in embryonic neural stem cells

Platelet-derived growth factor (PDGF) is important in central nervous system (CNS) development, and aberrant expression of PDGF and its receptors has been linked to developmental defects and brain tumorigenesis. We previously found that neural stem and progenitor cells in culture produce PDGF and respond to it by autocrine and/or paracrine signaling. We therefore aimed to examine CNS development after PDGF overexpression in neural stem cells in vivo. Transgenic mice were generated with PDGF-B under control of a minimal nestin enhancer element, which is specific for embryonic expression and will not drive adult expression in mice. The resulting mouse showed increased apoptosis in the developing striatum, which suggests a disturbed regulation of progenitor cells. Later in neurodevelopment, in early postnatal life, mice displayed enlarged lateral ventricles. This enlargement remained into adulthood and it was more pronounced in male mice than in transgenic female mice. Nevertheless, there was an overall normal composition of cell types and numbers in the brain and the transgenic mice were viable and fertile. Adult transgenic males, however, showed behavioral aberrations and locomotor dysfunction. Thus, a tightly regulated expression of PDGF during embryogenesis is required for normal brain development and function in mice.

Studies on the role of platelet-derived growth factor (PDGF) in human meningiomas

Over-expression of platelet-derived growth factor is critically involved in the development of a number of tumor types. Expression of PDGF and its receptors PDGFR-α and PDGFR-β has also been shown in previous studies in human meningiomas. We have investigated the expression, functional role and some aspects of mechanism of action of PDGF isoforms (PDGF-AA, PDGF-AB, PDGF-BB) and PDGF-receptors in tissue and primary cell cultures of 25 human meningiomas. Immunohistochemical studies of the meningiomas showed that most tumors expressed PDGF-β-receptors, whereas PDGF-α-receptors could be found in only a few tumors. In studies in meningioma cell cultures, PDGF isoforms had a heterogeneous effect on cell proliferation and only in few cases a significant stimulation was observed. PDGF-AA, PDGF-AB or PDGF-BB also variably influenced the mRNA synthesis and secretion of vascular endothelial growth factors VEGF121 and VEGF165 and mostly inhibited VEGF secretion. This was somewhat surprising since we observed, that PDGF isoforms activated the PI3 kinase/mTOR signaling pathway and enhanced the production of a downstream target of mTOR, hypoxia-inducible factor-1α, which is a transcription factor strongly inducing VEGF production. Due to the poor tumorigenic effects of PDGF isoforms, Gleevec, a PDGF receptor tyrosine kinase inhibitor had only poor anti-tumorigenic effects in meningioma cell cultures. In contrast, the mTOR inhibitor RAD001 and the plant compound curcumin strongly suppressed the proliferation of meningioma cells indicating that these substances are promising tools for the development of pharmacological treatment concepts of meningiomas.

Phase II Study of Imatinib in Unresectable Hepatocellular Carcinoma

The expression of platelet-derived growth factor, a potent mitogen, and its receptor both in tissue and serum correlate with the severity of liver cirrhosis. Over-expression of platelet-derived growth factor has been demonstrated in human hepatocellular carcinoma (HCC) tumors and cell lines. Imatinib, a potent inhibitor of BCR-ABL and c-kit, also inhibits the platelet-derived growth factor receptor tyrosine kinase. The trial was designed to assess the efficacy and safety of imatinib in patients with unresectable HCC. Eligibility criteria consisted of HCC patient over the age of 18 with reasonable organ function, unresectable but measurable disease, not candidates for chemoinfusion, and a performance status of 0 to 2. Imatinib was started at 300 mg/d orally with 100 mg/wk dose escalation up to 800 mg/d if toxicity permitted. Fifteen patients, median age 58 years, were enrolled and treated with imatinib. Most, or 7, patients had hepatitis B virus as a risk factor for HCC, followed by hepatitis C virus in 3 patients. Metastatic disease (American Joint Committee on Cancer stage IV) was noted in 13 patients and locally advanced (stage III) in the remainder. The median dose-level of imatinib was 500 mg/d. Two patients had stable disease lasting more than 2 months. The remainder progressed within 2 months of initiation of imatinib. No grade 3 or 4 hematologic toxicity was observed. Two patients had grade 3 elevated liver function tests during treatment; otherwise, there was no other grade 3 or 4 nonhematologic toxicity noted. Although toxicities were tolerable, imatinib as a monotherapy for the treatment of unresectable HCC has little, if any, significant efficacy.

Spectrum of Activity and Mechanism of Action of VEGF/PDGF Inhibitors

Angiogenesis plays an important role in tumor growth and metastasis. We review the function of the vascular endothelial growth factor (VEGF) in vessel formation that is complemented by platelet-derived growth factor (PDGF). We also review the agents designed to target VEGF, PDGF, and/or their receptors. VEGF plays a central role in tumor angiogenesis. It is expressed at increased levels in colorectal, liver, lung, thyroid, breast, as well as in bladder, ovary, uterine cancers, and in angiosarcomas, germ cell tumors, intracranial tumors, and others. VEGF blockade has been shown to have a direct and rapid antivascular effect in both animal and human tumors, through deprivation of tumor vascular supply and inhibition of endothelial proliferation. Overexpression of PDGFs and their receptors has also been reported in many types of cancers such as prostate, ovarian, and non-small-cell lung cancer. Many VEGF and PDGF inhibitors are available. The use of some of these inhibitors has significantly improved the survival of cancer patients. Several agents are in development and currently are being tested in clinical trials. Angiogenic agents inhibiting VEGF and PDGF have shown promising clinical results. Targeting more than one pathway by combining different agents may increase the antitumor activity of these drugs. The implementation of reliable radiologic and pathologic angiogenesis monitoring techniques is necessary to implement antiangiogenic therapies in cancer.

Pigment Epithelium-Derived Factor Inhibits Neointimal Hyperplasia after Vascular Injury by Blocking NADPH Oxidase-Mediated Reactive Oxygen Species Generation

Pigment epithelium-derived factor (PEDF) inhibits cytokine-induced endothelial cell activation through its antioxidative properties. However, the effect of PEDF on restenosis remains to be elucidated. Because the pathophysiological feature of restenosis is characterized by increased superoxide formation and accumulation of smooth muscle cells (SMCs), PEDF may inhibit this process via suppression of reactive oxygen species generation. We investigated here whether PEDF could prevent neointimal formation after balloon injury. PEDF levels were decreased in balloon-injured arteries. Adenoviral vector encoding human PEDF (Ad-PEDF) prevented neointimal formation. Expression and superoxide generation of the membrane components of NADPH oxidase, p22(phox) and gp91(phox), in the neointima were also suppressed by Ad-PEDF. Ad-PEDF reduced G(1) cyclin (cyclin D1 and E) expression and increased p27, a cyclin-dependent kinase inhibitor. In vitro, PEDF inhibited platelet-derived growth factor-BB-induced SMC proliferation and migration by blocking reactive oxygen species generation through suppression of NADPH oxidase activity via down-regulation of p22(PHOX) and gp91(PHOX). PEDF down-regulated G(1) cyclins and up-regulated p27 levels in platelet-derived growth factor-BB-exposed SMCs as well. These results demonstrate that PEDF could inhibit neointimal formation via suppression of NADPH oxidase-mediated reactive oxygen species generation. Our present study suggests that substitution of PEDF may be a novel therapeutic strategy for restenosis after balloon angioplasty.

Platelet Derived Growth Factor Overexpression is Gliomagenic

Platelet Derived Growth Factor Overexpression is Gliomagenic

Effects of isoliensinine on angiotensin II-induced proliferation of porcine coronary arterial smooth muscle cells

The inhibitory effects of isoliensinine (IL), a bisbenzylisoquinoline alkaloid extracted from the seed embryo of the traditional chinese medicinal herb Nelumbo nucifera Gaertn, on the proliferation of porcine coronary arterial smooth muscle cells (CASMCs) induced by angiotensin II(Ang II) and its mechanisms of action were investigated. Counting cultured cell number, MTT assay, immunohistochemical method and Western blot were adopted. Ang II 0.1 μmol l− 1 significantly evoked CASMC proliferation by 42%, which could be dose-dependently inhibited by IL 0.01–3 μmol l− 1 and the percentage of inhibition of IL 0.1 μmol l− 1 was 25%. Irbesartan (Irb) 0.1 μmol l− 1 inhibited CASMC proliferation by 22%. IL or Irb 0.1 μmol l− 1 decreased Ang II-induced overexpression of Platelet-derived growth factor (PDGF)-β and basic fibroblast growth factor (bFGF), respectively. Both of them also declined c-fos, c-myc and hsp70 overexpression, respectively. At the same concentration, the inhibitory effects of IL on PDGF-β were even stronger than those of Irb (P < 0.05). In summary, the data showed that IL possesses an anti-proliferative effect, which is related to the decrease of the overexpression of growth factors PDGF-β, bFGF, proto-oncogene c-fos, c-myc and hsp70.

Serum PDGF-AB in Pleural Mesothelioma

Overexpression of platelet-derived growth factor (PDGF) has been observed in lung and pleural tumors. The aim of this study was to evaluate the diagnostic and prognostic role of serum PDGF in pleural mesothelioma (PM). Four groups of subjects were studied: 93 malignant PM patients, 33 primary non small cell lung cancer patients, 51 subjects exposed to asbestos, defined as high-risk controls, and 24 healthy controls. PDGF-AB mean concentration was higher in PM patients (45.8 ng/ml) than in high-risk controls (33.1 ng/ml) and healthy controls (26.8 ng/ml). Using the cut-off level of 49.8 ng/ml, corresponding to the mean + 2SD of PDGF-AB in healthy controls, 43% of PM patients showed positive PDGF-AB levels. Survival was evaluated in 82 PM patients. At the end of the follow-up (median 9.8 months) 80.5% of patients had died. Median survival was 13.1 and 7.9 months for patients with PDGF-AB lower and higher than the cut-off, respectively. Adjusting for age, sex, histology and platelet count, positive PDGF-AB levels were associated with lower survival (OR = 1.2, 95%CI: 0.9–1.6), even if not significantly so. In conclusion, serum PDGF may represent a useful additional parameter to prognostic factors already available for PM.

Over-expression of platelet-derived growth factor in human diabetic nephropathy.

The pathogenetic mechanisms responsible for progressive renal impairment of diabetic nephropathy are still poorly understood, despite its growing incidence. Increasing evidence suggests that growth factors may contribute to the initiation and progressive fibrosis of diabetic nephropathy. In this study, the gene expression and protein distribution of platelet-derived growth factor-A and -B (PDGF-A and PDGF-B) in human diabetic nephropathy were examined. PDGF-A and PDGF-B mRNA levels in surplus renal biopsy tissue from seven patients with overt diabetic nephropathy and six nephrectomy samples were examined using quantitative reverse transcription-polymerase chain reaction (RT-PCR). In addition, each sample was also examined immunohistochemically to quantify and localize peptide expression of each PDGF isoform. Gene expression of PDGF-A and PDGF-B mRNA were increased 22- and 6-fold, respectively, in biopsies from patients with diabetic nephropathy compared with control tissue. Immunostaining also demonstrated increased peptide expression of both PDGF-A and PDGF-B in diabetic nephropathy, with each isoform showing a specific pattern of tissue distribution. The findings of increased gene and protein expression of PDGF in renal biopsies from patients with diabetic nephropathy imply a potential role for this prosclerotic growth factor in the development of the progressive fibrosis that characterizes human diabetic kidney disease.

Photoreceptor-specific overexpression of platelet-derived growth factor induces proliferation of endothelial cells, pericytes, and glial cells and aberrant vascular development: an ultrastructural and immunocytochemical study

Platelet-derived growth factor (PDGF) is necessary for the normal development of the retinal vasculature and its overexpression is likely to contribute to proliferative retinal disorders, such as proliferative vitreoretinopathy. Transgenic mice that overexpress PDGF-B in the photoreceptors (rho/PDGF-B mice) develop traction retinal detachment. In the present study, a detailed histopathological analysis was performed in rho/PDGF-B mice. In these transgenic mice, endothelial cells, pericytes, and glial cells begin to proliferate at postnatal day 7 (P7). All three cell types increase in numbers, forming a highly vascularized cell mass, which reaches a maximum thickness at P14. Cords of endothelial cells and glia invade the retina and exert traction, generating retinal folds; however, the deep capillary bed never forms. Griffonia simplicifolia isolectin B4 (GSA)-positive endothelial cells form tubes and penetrate the retina to the level of the outer plexiform layer, but they never interconnect to form the deep capillary bed. The vessels within the cell mass are patent, but have a very immature morphology. They often are thin-walled with fenestrations. Pericytes and glial cells are usually found in clusters and are not associated with the abnormal vessels. The lack of this association may account for the failure to form a mature vasculature.