Search

Ischemic stroke induces neovascularization of the injured tissue as an attempt to promote structural repair and neurological recovery. Angiogenesis is regulated by pericytes that potently react to ischemic stroke stressors, ranging from death to dysfunction. Platelet-derived growth factor (PDGF) receptor (PDGFR)β controls pericyte survival, migration, and interaction with brain endothelial cells. PDGF-D a specific ligand of PDGFRβ is expressed in the brain, yet its regulation and role in ischemic stroke pathobiology remains unexplored. Using experimental ischemic stroke mouse model, we found that PDGF-D is transiently induced in brain endothelial cells at the injury site in the subacute phase. To investigate the biological significance of PDGF-D post-ischemic stroke regulation, its subacute expression was either downregulated using siRNA or upregulated using an active recombinant form. Attenuation of PDGF-D subacute induction exacerbates neuronal loss, impairs microvascular density, alters vascular permeability, and increases microvascular stalling. Increasing PDGF-D subacute bioavailability rescues neuronal survival and improves neurological recovery. PDGF-D subacute enhanced bioavailability promotes stable neovascularization of the injured tissue and improves brain perfusion. Notably, PDGF-D enhanced bioavailability improves pericyte association with brain endothelial cells. Cell-based assays using human brain pericyte and brain endothelial cells exposed to ischemia-like conditions were applied to investigate the underlying mechanisms. PDGF-D stimulation attenuates pericyte loss and fibrotic transition, while increasing the secretion of pro-angiogenic and vascular protective factors. Moreover, PDGF-D stimulates pericyte migration required for optimal endothelial coverage and promotes angiogenesis. Our study unravels new insights into PDGF-D contribution to neurovascular protection after ischemic stroke by rescuing the functions of pericytes. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor-D (PDGF-D) is abundantly expressed in ocular diseases. Yet, it remains unknown whether and how PDGF-D affects ocular cells or cell-cell interactions in the eye. In this study, using single-cell RNA sequencing (scRNA-seq) and a mouse model of PDGF-D overexpression in retinal pigment epithelial (RPE) cells, we found that PDGF-D overexpression markedly upregulated the key immunoproteasome genes, leading to increased antigen processing/presentation capacity of RPE cells. Also, more than 6.5-fold ligand-receptor pairs were found in the PDGF-D overexpressing RPE-choroid tissues, suggesting markedly increased cell-cell interactions. Moreover, in the PDGF-D-overexpressing tissues, a unique cell population with a transcriptomic profile of both stromal cells and antigen-presenting RPE cells was detected, suggesting PDGF-D-induced epithelial-mesenchymal transition of RPE cells. Importantly, administration of ONX-0914, an immunoproteasome inhibitor, suppressed choroidal neovascularization (CNV) in a mouse CNV model in vivo. Together, we show that overexpression of PDGF-D increased pro-angiogenic immunoproteasome activities, and inhibiting immunoproteasome pathway may have therapeutic value for the treatment of neovascular diseases.

Background: Platelet derived growth factors (PDGF)‐D and the expression of its receptor increase in neoplastic progression of cancer. Co‐silencing of growth factor and receptor can be suggested as an important strategy for effective cancer therapy. In the present study, we hypothesized that suppression of PDGF‐D signaling pathway with small interfering RNAs (siRNAs) targeting both PDGF‐D and PDGF receptor (PDGFR)‐β is a promising strategy for anticancer therapy. Methods: Chitosan nanoplexes containing dual and single siRNA were prepared at different weight ratios and controlled by gel retardation assay. Characterization, cellular uptake, gene silencing and invasion studies were performed. The effect of nanoplexes on breast tumor growth, PDGF expression and apoptosis was investigated. Results: We have shown that downregulation of PDGF‐D and PDGFR‐β with chitosan/siRNA nanoplex formulations reduced proliferation and invasion in breast cancer cells. In the in vivo breast tumor model, it was determined that the intratumoral administration of chitosan/siPDGF‐D/siPDGFR‐β nanoplexes markedly decreased the tumor volume and PDGF‐D and PDGFR‐β mRNA and protein expression levels and increased apoptosis. Conclusions: According to the results obtained, we evaluated the effect of PDGF‐D and PDGFR‐β on breast tumor development and showed that RNAi‐mediated inhibition of this pathway formulated with chitosan nanoplexes can be considered as a new breast cancer therapy strategy. [ABSTRACT FROM AUTHOR]

Abstract Background Glioblastoma multiforme (GBM), a lethal brain tumor, remains the most daunting challenge in cancer therapy. Overexpression and constitutive activation of PDGFs and PDGFRα are observed in most GBM; however, available inhibitors targeting isolated signaling pathways are minimally effective. Therefore, better understanding of crucial mechanisms underlying GBM is needed for developing more effective targeted therapies. Methods Target genes controlled by HIF1α in GBM were identified by analysis of TCGA database and by RNA-sequencing of GBM cells with HIF1α knockout by sgRNA-Cas9 method. Functional roles of HIF1α, PDGFs and PDGFRs were elucidated by loss- or gain-of-function assays or chemical inhibitors, and compared in response to oxygen tension. Pharmacological efficacy and gene expression in mice with intracranial xenografts of primary GBM were analyzed by bioluminescence imaging and immunofluorescence. Results HIF1α binds the PDGFD proximal promoter and PDGFRA intron enhancers in GBM cells under normoxia or mild-hypoxia to induce their expression and maintain constitutive activation of AKT signaling, which in turn increases HIF1α protein level and activity. Paradoxically, severe hypoxia abrogates PDGFRα expression despite enhancing HIF1α accumulation and corresponding PDGF-D expression. Knockout of HIF1A, PDGFD or PDGFRA in U251 cells inhibits cell growth and invasion in vitro and eradicates tumor growth in vivo. HIF1A knockdown in primary GBM extends survival of xenograft mice, whereas PDGFD overexpression in GL261 shortens survival. HIF1α inhibitor Echinomycin induces GBM cell apoptosis and effectively inhibits growth of GBM in vivo by simultaneously targeting HIF1α-PDGFD/PDGFRα-AKT feedforward pathway. Conclusions HIF1α orchestrates expression of PDGF-D and PDGFRα for constitutive activation of AKT pathway and is crucial for GBM malignancy. Therefore, therapies targeting HIF1α should provide an effective treatment for GBM.

ObjectiveInflammation plays a key role in the pathophysiological processes after intracerebral hemorrhage (ICH). Post-ICH macrophages infiltrate the brain and release pro-inflammatory factors (tumor necrosis factor-α), amplifying microglial activation and neutrophil infiltration. Platelet-derived growth factor receptor-β (PDGFR-β) is expressed on macrophages and it's activation induces the recruitment of macrophages. Platelet-derived growth factor-D (PDGF-D) is an agonist with a significantly higher affinity to the PDGFR-β compared to another isoform of the receptor. In this study, we investigated the role of PDGF-D in the pro-inflammatory response after ICH in mice.MethodsA blood injection model of ICH was used in eight-week old male CD1 mice (weight 30g). Some mice received an injection of plasmin or PDGF-D. Gleevec, a PDGFR inhibitor, was administered at 1, 3 or 6h post-ICH. Plasmin was administered with or without PDGF-D siRNAs mixture or scramble siRNA. A plasmin-antagonist, ε-Aminocaproic acid (EACA), was co-administrated with the blood. The effects of ICH and treatment on the brain injury and post-ICH inflammation were investigated.ResultsICH resulted in the overexpression of PDGF-D, associated with the infiltration of macrophages. PDGFR-inhibition decreased ICH-induced brain injury, attenuating macrophage and neutrophil infiltration, reducing microglial activation and TNF-α production. Administration of recombinant PDGF-D induced TNF-α production, and PDGFR-inhibition attenuated it. A plasmin-antagonist suppressed PDGFR-β activation and microglial activation. Plasmin increased PDGF-D expression, and PDGF-D inhibition reduced neutrophil infiltration.ConclusionICH-induced PDGF-D accumulation contributed to post-ICH inflammation via PDGFR activation and enhanced macrophage infiltration. The inhibition of PDGFR had an anti-inflammatory effect. Plasmin is a possible upstream effector of PDGF-D. The targeting of PDGF-D may provide a novel way to decrease brain injury after ICH.

The axis of platelet-derived growth factor (PDGF) and PDGF receptor-beta (PDGFRß) plays prominent roles in cell growth and motility. In addition, PDGF-D enhances human natural killer (NK) cell effector functions when binding to the NKp44 receptor. Here, we report an additional but previously unknown role of PDGF-D, whereby it mediates interleukin-15 (IL-15)-induced human NK cell survival but not effector functions via its binding to PDGFRß but independent of its binding to NKp44. Resting NK cells express no PDGFRß and only a low level of PDGF-D, but both are significantly up-regulated by IL-15, via the nuclear factor B signaling pathway, to promote cell survival in an autocrine manner. Both ectopic and IL-15-induced expression of PDGFRß improves NK cell survival in response to treatment with PDGF-D. Our results suggest that the PDGF-D2PDGFRß signaling pathway is a mechanism by which IL-15 selectively regulates the survival of human NK cells without modulating their effector functions. [ABSTRACT FROM AUTHOR]

Background: Glioblastoma multiforme (GBM), a lethal brain tumor, remains the most daunting challenge in cancer therapy. Overexpression and constitutive activation of PDGFs and PDGFRα are observed in most GBM; however, available inhibitors targeting isolated signaling pathways are minimally effective. Therefore, better understanding of crucial mechanisms underlying GBM is needed for developing more effective targeted therapies. Methods: Target genes controlled by HIF1α in GBM were identified by analysis of TCGA database and by RNA-sequencing of GBM cells with HIF1α knockout by sgRNA-Cas9 method. Functional roles of HIF1α, PDGFs and PDGFRs were elucidated by loss- or gain-of-function assays or chemical inhibitors, and compared in response to oxygen tension. Pharmacological efficacy and gene expression in mice with intracranial xenografts of primary GBM were analyzed by bioluminescence imaging and immunofluorescence. Results: HIF1α binds the PDGFD proximal promoter and PDGFRA intron enhancers in GBM cells under normoxia or mild-hypoxia to induce their expression and maintain constitutive activation of AKT signaling, which in turn increases HIF1α protein level and activity. Paradoxically, severe hypoxia abrogates PDGFRα expression despite enhancing HIF1α accumulation and corresponding PDGF-D expression. Knockout of HIF1A, PDGFD or PDGFRA in U251 cells inhibits cell growth and invasion in vitro and eradicates tumor growth in vivo. HIF1A knockdown in primary GBM extends survival of xenograft mice, whereas PDGFD overexpression in GL261 shortens survival. HIF1α inhibitor Echinomycin induces GBM cell apoptosis and effectively inhibits growth of GBM in vivo by simultaneously targeting HIF1α-PDGFD/PDGFRα-AKT feedforward pathway. Conclusions: HIF1α orchestrates expression of PDGF-D and PDGFRα for constitutive activation of AKT pathway and is crucial for GBM malignancy. Therefore, therapies targeting HIF1α should provide an effective treatment for GBM. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor-D (PDGF-D) is highly expressed in immune cells. However, the potential role of PDGF-D in immune system remains thus far unclear. Here, we reveal a novel function of PDGF-D in activating both classical and alternative complement pathways that markedly increase chemokine and cytokine responses to promote macrophage polarization. Pharmacological targeting of the complement C3a receptor using SB290157 alleviated PDGF-D-induced neuroinflammation by blocking macrophage polarization and inhibited pathological choroidal neovascularization. Our study thus suggests that therapeutic strategies targeting both PDGF-D and the complement system may open up new possibilities for the treatment of neovascular diseases.

Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome is a lifethreatening pregnancy complication. Though there are several medications widely used to treat HELLP syndrome, delivery is the only efficient treatment. The goal of the present study was to investigate the effects of platelet-derived growth factor-D (PDGF-D), a newly identified PDGF, in a rat model of HELLP syndrome which was acco mplished by sFlt-1 and sEng injection. The expression levels of PDGF-D in pregnant women diagnosed with HELLP syndrome was determined. A HELLP rat model was established and the PDGF-D expression level in the plasma and the placenta tissue was eval uated. To evaluate the effects of PDGF-D in HELLP syndrome model, siPDGF-D was injected into the rats and the HELLP syndrome-related parameters were measured. The levels of inflammatory cytokines and PDGF-D were determined by ELISA. The oxidative stress activities in the plasma were also determined. Furthermore, the expression of PDGF-D/PDGFR-β/nuclear factor κB (NF-κB) p65 in placenta tissues was evaluated by Western blotting. C ompared to the normal pregnant (NP) group, the levels of PDGF-D were au gmented regardless of species. Knockdown of PDGF-D can result in the alleviation o f HELLP syndrome development and progression in the HELLP rat model. Importantly, as a result of PDGF-D knockdown, the serum levels of inflammatory cytokines and oxidative stress activities were modulated, and the phosphorylation of PDGFR-β and NF-κB p65 in placenta tissue was inhibited. Taking together, our findings indicate that targeting PDGF-D could be used as a novel strategy to treat patients with HELLP syndrome. [ABSTRACT FROM AUTHOR]

Background: We explored the dynamic expression of platelet-derived growth factor-D (PDGF-D) and phosphorylated platelet-derived growth factor receptor-β (p-PDGFR-β) after traumatic brain injury in rats to provide theoretical basis for selecting therapeutic target and intervention time after traumatic brain injury. Methods: This study prepared the weight drop/impact acceleration-induced traumatic brain injury (TBI) model in rats, including sham group and TBI groups at different observation time points (6 hours, 12 hours, 24 hours, 3 days, and 7 days after TBI). The dynamic expression of PDGF-D and p-PDGFR-β after TBI were detected by western blot and immunofluorescence staining. Results: The expression level of PDGF-D and p-PDGFR-β after TBI was detected by western blot. The PDGF-D level was increased (p < 0.05) 6 hours after TBI and remained at the high level until 3 days after TBI (p < 0.05). The p-PDGFR-β level was increased (p < 0.05) 12 hours after TBI and remained at the high level until 3 days after TBI (p < 0.05). PDGF-D and p-PDGFR-β in brain tissues were found by immunofluorescence in the perihematoma area 24 hours after TBI. Conclusions: This study revealed the expression phenomenon of PDGF-D and p-PDGFR-β after TBI in rats, suggesting that PDGF-D participates in the process of secondary brain injury after TBI through specific binding with PDGFR-β, which provides a theoretical basis for further research on selecting therapeutic targets and intervention times after TBI. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor D (PDGF-D) has been shown to mediate cellular processes of importance in cancer progression. This study aimed to investigate the expression and putative involvement of PDGF-D signaling in colorectal carcinogenesis. PDGF-D was expressed in vascular endothelial cells in tumor and normal tissues. PDGF-D stimulation of cells altered genes of importance in carcinogenic processes. In addition, PDGF-D increased the proliferation rate while imatinib inhibited these effects. PDGF-D and its PDGF receptor beta (PDGFR-β) are expressed in colorectal cancer and blockage of PDGF-D/PDGFR-β signaling using tyrosine kinase inhibitors, such as imatinib, might be important in inhibiting tumor-promoting actions. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the correlation between the platelet-derived growth factor-D (PDGF-D) gene and sheep tail type character and explore the potential underlying mechanism. A total of 533 sheep were included in this study. Polymorphic sites were examined by Pool-seq, and individual genotype identification and correlation analysis between tail type data were conducted using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF-MS) method. JASPART website was used to predict transcription factor binding sites in the promoter region with and without PDGF-D gene mutation. The effect of PDGF-D on adipogenic differentiation of sheep preadipocytes was investigated. Two single nucleotide polymorphism sites were identified: g.4122606 C > G site was significantly correlated with tail length, and g.3852134 C > T site was significantly correlated with tail width. g.3852134 C > T was located in the promoter region. Six transcription factor binding sites were eliminated after promoter mutation, and three new transcription factor binding sites appeared. Expression levels of peroxisome proliferator-activated receptor gamma (PPARγ) and lipoproteinlipase (LPL) were significantly up-regulated upon PDGF-D overexpression. Oil red O staining showed increased small and large oil drops in the PDGF-D overexpression group. Together these results indicate the PDGF-D gene is an important gene controlling sheep tail shape and regulating sheep tail fat deposition to a certain degree.

The cardiovascular system is among the first organs formed during development and is pivotal for the formation and function of the rest of the organs and tissues. Therefore, the function and homeostasis of the cardiovascular system are finely regulated by many important molecules. Extensive studies have shown that platelet-derived growth factors (PDGFs) and their receptors are critical regulators of the cardiovascular system. Even though PDGF-C and PDGF-D are relatively new members of the PDGF family, their critical roles in the cardiovascular system as angiogenic and survival factors have been amply demonstrated. Understanding the functions of PDGF-C and PDGF-D and the signaling pathways involved may provide novel insights into both basic biomedical research and new therapeutic possibilities for the treatment of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor-D (PDGF-D) is abundantly expressed in ocular diseases. Yet, it remains unknown whether and how PDGF-D affects ocular cells or cell-cell interactions in the eye. In this study, using single-cell RNA sequencing (scRNA-seq) and a mouse model of PDGF-D overexpression in retinal pigment epithelial (RPE) cells, we found that PDGF-D overexpression markedly upregulated the key immunoproteasome genes, leading to increased antigen processing/presentation capacity of RPE cells. Also, more than 6.5-fold ligand-receptor pairs were found in the PDGF-D overexpressing RPE-choroid tissues, suggesting markedly increased cell-cell interactions. Moreover, in the PDGF-D-overexpressing tissues, a unique cell population with a transcriptomic profile of both stromal cells and antigen-presenting RPE cells was detected, suggesting PDGF-D-induced epithelial-mesenchymal transition of RPE cells. Importantly, administration of ONX-0914, an immunoproteasome inhibitor, suppressed choroidal neovascularization (CNV) in a mouse CNV model in vivo . Together, we show that overexpression of PDGF-D increased pro-angiogenic immunoproteasome activities, and inhibiting immunoproteasome pathway may have therapeutic value for the treatment of neovascular diseases., (© 2023 The Authors.)

Background: Platelet-derived growth factor (PDGF) D has been reported to be active in fibroblasts, and in areas of myocardial infarction. In this longitudinal study we evaluated the association between PDGF-D polymorphism and cardiovascular mortality, and attempted to discover whether specific genotype differences regarding risk could be observed, and if gender differences could be seen. Methods: Four hundred seventy-six elderly community participants were included in this study. All participants underwent a clinical examination, echocardiography, and blood sampling including PDGF-D single nucleotide polymorphism (SNP) analyses of the rs974819 A/A, G/A and G/G SNP. The follow-up time was 6.7 years. Results: No specific genotype of rs974819 demonstrated increased cardiovascular mortality in the total population, however, the male group with genotypes A/A and G/A demonstrated an increased risk that persisted in a multivariate evaluation where adjustments were made for well-known cardiovascular risk factors (2.7 fold compared with the G/G genotype). No corresponding finding was observed in the female group. Conclusion: We report here for the first time that the genotypes G/A or A/A of the SNP rs974819 near PDGF-D exhibited a 2.7 fold increased cardiovascular mortality risk in males. Corresponding increased risk could not be observed in either the total population and thus not in the female group. However, the sample size is was small and the results should be regarded as hypothesis-generating, and thus more research in the field is recommended. [ABSTRACT FROM AUTHOR]

Activation of α-platelet-derived growth factor receptor (β-PDGFR) is associated with prostate cancer (PCa) progression and recurrence after prostatectomy. Analysis of the β-PDGFR ligands in PCa revealed association between PDGF-D expression and Gleason score as well as tumor stage. During the course of studying the functional consequences of PDGF ligand-specific β-PDGFR signaling in PCa, we discovered a novel function of PDGF-D for activation/shedding of the serine protease matriptase leading to cell invasion, migration, and tumorigenesis. The present study showed that PDGF-D, not PDGF-B, induces extracellular acidification, which correlates with increased matriptase activation. A cDNA microarray analysis revealed that PDGF-D/β-PDGFR signaling upregulates expression of the acidosis regulator carbonic anhydrase IX (CAIX), a classic target of the transcriptional factor hypoxia-inducible factor-1α (HIF-1α). Cellular fractionation displayed a strong HIF-1α nuclear localization in PDGFD- expressing cells. Treatment of vector control or PDGF-B-expressing cells with the HIF-1α activator CoCl2 led to increased CAIX expression accompanied by extracellular acidosis and matriptase activation. Furthermore, the analysis of the CAFTD cell lines, variants of the BPH-1 transformation model, showed that increased PDGF-D expression is associated with enhanced HIF-1α activity, CAIX induction, cellular acidosis, and matriptase shedding. Importantly, shRNAmediated knockdown of CAIX expression effectively reversed extracellular acidosis and matriptase activation in PDGF-D-transfected BPH-1 cells and in CAFTD variants that express endogenous PDGF-D at a high level. Taken together, these novel findings reveal a new paradigm in matriptase activation involving PDGF-D-specific signal transduction leading to extracellular acidosis. [ABSTRACT FROM AUTHOR]

Increasing attention has been focused on the malignant tumor microenvironment, which plays important roles in tumor occurrence, progression and metastasis. Fibroblasts are recruited by platelet-derived growth factor (PDGFs) and invade the tumor microenvironment. In the PDGF family, PDGF-B has been reported to play an important role in the recruitment and invasion programs. However, whether PDGF-D plays a role in these programs remains unclear. We generated a recombinant plasmid expressing human PDGF-D and transfected the plasmid to dermal fibroblasts to examine the effects on cell invasive activities in 3D type I collagen gels. PDGF-D plasmid transfection enhanced fibroblast invasive activities both in invasive cell numbers and invasion depth in 3D collagen gels. These effects were blocked by Snail-specific siRNA transfection. PDGF-D transfection significantly induced Snail expression at both mRNA and protein levels. PDGF-D further upregulated MT1-MMP mRNA and protein expressions and this was inhibited when Snail was knocked down by siRNA. Both Snail and MT1-MMP expressions in fibroblasts and cellular invasive activities in 3D collagen induced by PDGF-D were inhibited by LY294002, SP600125, and U1026, the inhibitors of PI3K, JNK, and ERK1/2 signaling pathways, respectively. However, no effects were observed in response to the P38MAPK signaling pathway inhibitor SB203580. These effects of PDGF-D were confirmed by using the culture supernatants of the transfectants. Taken together, these data demonstrate that PDGF-D plays important roles in the recruitment and invasion programs of fibroblasts via the activation of PI3K, JNK and ERK1/2 signaling pathways, and upregulation of Snail and downstream effecter MT1-MMP. These findings indicate that PDGF-D is an important player in the tumor microenvironment for fibroblast recruitment. [ABSTRACT FROM AUTHOR]

Background: Gene therapeutics are being developed to treat metastatic breast tumors, which are mostly resistant to conventional therapies. Targeting platelet-derived growth factor-D (PDGF-D) is a viable approach because it is known to play roles in angiogenesis and tumor growth. The success of gene therapy is largely dependent on delivery vectors, but both viral and nonviral delivery vectors have their disadvantages. Evolving hybrid vectors are being used to overcome those disadvantages., Objectives: In this study, we aimed to prepare a recombinant adenovirus type-5 (Ad5)/chitosan hybrid vector to deliver shPDGF-D in a breast cancer cell line by the noncovalent coating of the Ad5 surface with chitosan, a natural polymer., Methods: The Ad5/chitosan hybrid vector was prepared by the noncovalent coating of the Ad5 surface with different molecular weights (low and high) and different amounts of chitosan (12.5, 25, and 50 μg), and the effect of silencing PDGF-D was investigated in the MDA-MB-231 cell line., Results: In vitro characterization studies showed that the noncovalent chitosan coating increased the size of the Ad5 particle and changed the surface charge from -16.53 mV to slightly neutral. In vitro cell culture studies also showed that the addition of chitosan with both low (73.61%) and high (65.86%) molecular weight increased the PDGF-D silencing efficiency of the Ad5 vector (42.44%) at 48 hours. While low-molecular-weight chitosan had faster effects, high-molecular-weight chitosan provided a more sustained effect in PDGF-D silencing., Conclusion: The results indicate that noncovalent chitosan modification may improve the therapeutic effects of the Ad5 vector, offering the potential for further in vitro and in vivo experiments., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Platelet-derived growth factor-D (PDGF-D) is one member of PDGF growth factors and known to signal by binding to and activating its cognate receptor type β (PDGFR-β). Beside PDGF-B, PDGF-D is a potent growth factor for stellate cell growth and proliferation and therefore potentiates the extracellular matrix deposition in liver fibrogenesis. We aimed to explore the signaling and molecular mechanisms of PDGF-D in liver fibrogenesis using the primary liver portal myofibroblasts and hepatic stellate cells. Unexpectedly we found PDGF-D to bind to PDGFR-α, thus inducing receptor endocytosis and decreasing the amount of PDGFR-α significantly. PDGF-D activates PDGFR-α specific tyrosine 754 and -1018 phosphorylation and CrkII, the adaptor protein that is specifically recruited by activated PDGFR-α. As a novel finding we could also demonstrate that recombinant PDGFR-α-Fc chimera homodimer is able to bind PDGF-D and thus prevent PDGF-D signaling. PDGF-D does induce individual PDGFR-β specific tyrosine phosphorylation similar to the PDGF-B. Additionally, PDGF-D enhances extracellular matrix accumulation comparable to the PDGF-B isoform. Conclusion PDGF-D signaling in pMF and HSC is identical to that of PDGF-B by binding to both PDGFR-α and -β. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor-D (PDGF-D) was recently identified, and acts as potent mitogen for mesenchymal cells. PDGF-D also induces cellular transformation and promotes tumor growth. However, the functional role of PDGF-D in adipose-derived stem cells (ASCs) has not been identified. Therefore, we primarily investigated the autocrine and paracrine roles of PDGF-D in this study. Furthermore, we identified the signaling pathways and the molecular mechanisms involved in PDGF-D-induced stimulation of ASCs. It is of interest that PDGF-B is not expressed, but PDGF-D and PDGF receptor-β are expressed in ASCs. PDGF-D showed the strongest mitogenic effect on ASCs, and PDGF-D regulates the proliferation and migration of ASCs through the PI3K/Akt pathways. PDGF-D also increases the proliferation and migration of ASCs through generation of mitochondrial reactive oxygen species (mtROS) and mitochondrial fission. mtROS generation and fission were mediated by p66Shc phosphorylation, and BCL2-related protein A1 and Serpine peptidase inhibitor, clade E, member 1 mediated the proliferation and migration of ASCs. In addition, PDGF-D upregulated the mRNA expression of diverse growth factors such as vascular endothelial growth factor A, fibroblast growth factor 1 (FGF1), FGF5, leukemia inhibitory factor, inhibin, beta A, interleukin 11, and heparin-binding EGF-like growth factor. Therefore, the preconditioning of PDGF-D enhanced the hair-regenerative potential of ASCs. PDGF-D-induced growth factor expression was attenuated by a pharmacological inhibitor of mitogen-activated protein kinase pathway. In summary, PDGF-D is highly expressed by ASCs, where it acts as a potent mitogenic factor. PDGF-D also upregulates growth factor expression in ASCs. Therefore, PDGF-D can be considered a novel ASC stimulator, and used as a preconditioning agent before ASC transplantation. S tem C ells 2015;33:542-556 [ABSTRACT FROM AUTHOR]

Abstract: Platelet-derived growth factor-D (PDGF-D) signaling pathway has been reported to be involved in regulating various cellular processes, such as cell growth, apoptotic cell death, migration, invasion, angiogenesis and metastasis. Recently, multiple studies have shown that PDGF-D plays a critical role in governing epithelial-to-mesenchymal transition (EMT), although the underlying mechanism of PDGF-D-mediated acquisition of EMT is largely unclear. Therefore, this mini review will discuss recent advances in our understanding of the role of PDGF-D in the acquisition of EMT during tumorigenesis. Furthermore, we will summarize the function of chemical inhibitors and natural compounds that are known to inactivate PDGF-D signaling pathway, which leads to the reversal of EMT. In summary, inactivation of PDGF-D could be a novel strategy for achieving better treatment outcome of patients inflicted with cancers. [Copyright &y& Elsevier]

Background/Aims: Growth factors play a critical role in proliferation for a variety of cancer cells. The present study was conducted to understand the signaling cascades underlying PDGF-D/PDGF-ββ receptor-mediated proliferation of mesothelioma cells. Methods: Cell growth and cell cycle were analyzed in human non-malignant Met5A cells and malignant mesothelioma cells such as MSTO-211H, NCI-H28, NCI-H2052, and NCI-H2452 cells. Results: Growth of all the cells used here was not affected by PDGF-D, regardless of concentrations (1-30 ng/ml) or treatment time (48-72 h). Spontaneous growth of those cells was significantly inhibited by knocking-down PDGFD or PDGF-ββ receptor, without affecting cell cycling. The cell growth was significantly inhibited by the Akt inhibitor MK2206 and the ROCK inhibitor Y27632 for all the cell types, by the PDK1 inhibitor BX912 for NCI-H28 cells alone, and by the Rac1 inhibitor NSC23766 for NCI-H2052 cells alone, while the PI3 kinase inhibitor wortmannin had no effect. The cell growth, alternatively, was significantly attenuated by MAP kinase kinase inhibitor PD98059 or the ERK1/2 inhibitor FR180204 for all the cell types. Conclusion: The results of the present study show that PDGF-D promotes mesothelioma cell proliferation by targeting ROCK or MAP kinase through autocrine activation of PDGF-ββ receptor. [ABSTRACT FROM AUTHOR]

Platelet-derived growth factor-D (PDGF-D) has been linked with several human malignancies; however, its role in breast cancer progression is not known. We found that PDGF-D expressing breast cancer cell lines MDA-MB-231 and SUM-149 are more invasive compared to cell lines with little or no expression of PDGF-D such as MDA-MB-468 and MCF-7 cells. Over-expression of PDGF-D in PDGF-D low expressing MDA-MB-468 and MCF-7 cells by cDNA transfection showed increased cell proliferation while silencing the expression of PDGF-D by siRNA in PDGF-D high expressing MDA-MB-231 and SUM-149 cells showed decreased cell proliferation and increased apoptosis. Moreover, PDGF-D over-expression was positively correlated with the expression of Notch-1 and Jagged-1, and the expression of mesenchymal markers (Vimentin and ZEB-2) with concomitant decreased expression of epithelial marker E-cadherin. Since NF-κB activation plays a crucial role in Notch signaling as well as in epithelial-mesenchymal transition and tumor aggressiveness, we determined the DNA binding activity of NF-κB and our findings are consistent showing that PDGF-D over-expression led to increased DNA binding activity of NF-κB while it was found to be decreased by inactivation of PDGF-D. These results were also consistent with the expression and activity of MMP-9 and VEGF, as well as invasive characteristics. Further, forced expression of Notch-1/Jagged-1 by cDNA transfection de-repressed the effects of PDGF-D silencing on NF-κB activity and invasion. From these results, we conclude that PDGF-D plays an important role in breast tumor aggressiveness and this process is mechanistically linked with the activation of Notch and NF-κB signaling. [ABSTRACT FROM AUTHOR]

Abstract: Platelet-derived growth factor-D (PDGF-D) can regulate many cellular processes, including cell proliferation, apoptosis, transformation, migration, invasion, angiogenesis and metastasis. Therefore PDGF-D signaling has been considered to be important in human malignancies, and thus PDGF-D signaling may represent a novel therapeutic target, and as such suggests that the development of agents that will target PDGF-D signaling is likely to have a significant therapeutic impact on human cancers. This mini-review describes the mechanisms of signal transduction associated with PDGF-D signaling to support the role of PDGF-D in the carcinogenesis. Moreover, we summarize data on several PDGF-D inhibitors especially naturally occurring “chemopreventive agent” such an indole compound, which we believe could serve as a novel agent for the prevention of tumor progression and/or treatment of human malignancies by targeted inactivation of PDGF-D signaling. [Copyright &y& Elsevier]

Members of the platelet-derived growth factor (PDGF) family are mitogens for cells of mesenchymal origin and have important functions during embryonic development, blood vessel maturation, fibrotic diseases and cancer. In contrast to the two classical PDGFs, the novel and less well-characterized members, PDGF-CC and PDGF-DD, are latent factors that need to be processed extracellularly by activating proteases, before they can mediate PDGF receptor activation. Here, we elucidate the structural requirements for urokinase plasminogen activator (uPA)-mediated activation of PDGF-DD, as well as the intricate interplay with uPA receptor (uPAR) signalling. Furthermore, we show that activated PDGF-DD, in comparison to latent, more potently transforms NIH/3T3 cells in vitro. Conversely, xenograft studies in nude mice demonstrate that cells expressing latent PDGF-DD are more tumorigenic than those expressing activated PDGF-DD. These findings imply that a fine-tuned proteolytic activation, in the local milieu, controls PDGF-DD bioavailability. Moreover, we suggest that proteolytic activation of PDGF-DD reveals a retention motif mediating interactions with pericellular components. Our proposed mechanism, where uPA not only generates active PDGF-DD, but also regulates its spatial distribution, provides novel insights into the biological function of PDGF-DD.Oncogene (2009) 28, 534–544; doi:10.1038/onc.2008.410; published online 10 November 2008 [ABSTRACT FROM AUTHOR]

Summary: Chronic allograft nephropathy (CAN), a descriptive term denoting chronic scarring injury of the renal parenchyma and vasculature in allograft kidneys arising from various etiologies including chronic rejection, is the most common cause of late allograft failure, but mediators of this progressive injury largely remain unknown. We hypothesized that platelet-derived growth factor D (PDGF-D) and its specific receptor PDGF-Rβ may be an important mediator in the pathogenesis of CAN and, hence, sought to identify its expression in this setting. Allograft nephrectomies demonstrating CAN, obtained from patients with irreversible transplant kidney failure (n = 15), were compared with renal tissues without prominent histopathological abnormalities (n = 18) and a series of renal allograft biopsies demonstrating acute vascular rejection (AVR) (n = 12). Antibodies to PDGF-D and PDGF-Rβ were used for immunohistochemistry. Double and triple immunohistochemistry was used to identify cell types expressing PDGF-D. PDGF-D was widely expressed in most neointimas in arteries exhibiting the chronic arteriopathy of CAN and only weakly expressed in a small proportion of sclerotic arteries in the other 2 groups. Double and triple immunolabeling demonstrated that the neointimal cells expressing PDGF-D were α-smooth muscle actin–expressing cells, but not infiltrating macrophages or endothelial cells. PDGF-Rβ expression evaluated in serial sections was localized to the same sites where neointimal PDGF-D was expressed. PDGF-Rβ was expressed in interstitial cells more abundantly in the CAN group compared with the normal and AVR groups, without demonstrable colocalization of PDGF-D. PDGF-D is present in the neointima of the arteriopathy of CAN, where it can engage PDGF-Rβ to promote mesenchymal cell migration, proliferation, and neointima formation. PDGF-D may engage the PDGF-Rβ to promote interstitial injury in chronic allograft injury, but its sources within the interstitium were unidentified. [Copyright &y& Elsevier]

Background/Aims: We analyzed the expression of platelet-derived growth factor D (PDGF-D) in an experimental bile duct-ligated (BDL) rat model and assessed its biological function in cultured hepatic stellate cells (HSC) and myofibroblasts (MFB). Methods: The mRNA for PDGF-A, -B, -C, -D and for PDGF receptor-α and -β chains (PDGFRα and PDGFRβ) in normal and fibrotic rat livers was assessed quantitatively. Protein levels of PDGF-D were quantified by immunoblotting and immunohistochemistry. Results: The relative mRNA expression of all PDGF isoforms and receptors upregulated upon BDL and PDGF-A, -B and -D expression was significantly higher than that of PDGF-C. PDGF-D and PDGFRβ protein also increased markedly. Immunostaining revealed that PDGF-D is localized along the fibrotic septa of the periportal- and perisinusoidal areas. Besides PDGF-B, PDGF-D is the second most potent PDGF isoform in PDGFRβ signaling within HSC/MFB, evidenced by PDGFRβ autophosphorylation and activation of the downstream signaling molecules ERK1/2-, JNK-, p38 MAPK, and PKB/Akt while PDGF-C effects were minimal. PDGF-D exerted mitogenic and fibrogenic effects in both cultured HSC and MFB comparable to PDGF-B but PDGF-A and -C showed only marginal fibrogenic effects. Conclusions: PDGF-D possesses potential pathogenetic properties for HSC activation and matrix remodeling in liver fibrosis. [Copyright &y& Elsevier]

Abstract: In this study, we determined the role of PDGF-D, a new member of the PDGF family, in a rat model of balloon injured artery made with a 2F catheter in Sprague–Dawley male rats. PDGF-D expression was studied in the injured and control segments of abdominal aorta. The function of PDGF-D was evaluated in rat vascular smooth muscle cells stably transfected with PDGF-D gene. We found that in normal abdominal aorta, PDGF-D was highly expressed in adventia, moderate in endothelia, and unidentified in media. Stable transfection of PDGF-D gene into vascular smooth muscle cells increased the cell migration by 2.2-fold, and the proliferation by 2.3-fold, respectively, and MMP-2 production and activity as well. These results support the fact that PDGF-D is involved in the formation of neointimal hyperplasia induced by balloon catheter injury and may serve as a target in preventing vascular restenosis after coronary angioplasty. [Copyright &y& Elsevier]

Background: The platelet derived growth factor-D (PDGF-D) plays an important role in breast tumor aggressiveness. However, limited study has investigated the effect of silencing PDGF-D on the biological function of breast cancer. The purpose of this study is to clarify the potential value of PDGF-D as a target for breast cancer treatment., Methods: Reverse transcription-polymerase chain reaction and western blot were used to detect PDGF-D expression in 5 different breast cancer cells. The lentiviral vector was usd to silence PDGF-D in MDA-MB-231 cells. Then, Methyl Thiazolyl Tetrazolium was used to detect cell viability, 5-Ethynyl-2'- deoxyuridine and a soft agar assay were used to detect cell proliferation and clonality. Additionally, cell apoptosis after PDGF-D knockdown was measured by Annexin V/ Prodium Iodide staining, and cell migration was detected by trans-well assay. Survival rate and tumor size were measured by nude mice transplantation., Results: The MDA-MB-231 and SK-BR-3 cell lines showed higher PDGF-D expression than the MCF7 cell lines (P<.05). After the PDGF-D gene was silenced, the growth and colony forming abilitys ignificantly decreased (P<.05) together with the induction of apoptosis in MDA-MB-231 cells (P<.05). Moreover, MDA-MB-231 cells with PDGF-D silencing showed significantly diminished aggressive migration and invasion potential compared to other cells (P<.05). In vivo experiments also indicated that PDGF-D silencing inhibited tumor growth and improved the survival rate of tumor-bearing mice., Conclusion: Downregulation of PDGF-D had dramatic effects on breast cancer cell proliferation, apoptosis and migration, which indicates that it plays an important role in breast cancer development and progression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The axis of platelet-derived growth factor (PDGF) and PDGF receptor-beta (PDGFRβ) plays prominent roles in cell growth and motility. In addition, PDGF-D enhances human natural killer (NK) cell effector functions when binding to the NKp44 receptor. Here, we report an additional but previously unknown role of PDGF-D, whereby it mediates interleukin-15 (IL-15)-induced human NK cell survival but not effector functions via its binding to PDGFRβ but independent of its binding to NKp44. Resting NK cells express no PDGFRβ and only a low level of PDGF-D, but both are significantly up-regulated by IL-15, via the nuclear factor κB signaling pathway, to promote cell survival in an autocrine manner. Both ectopic and IL-15-induced expression of PDGFRβ improves NK cell survival in response to treatment with PDGF-D. Our results suggest that the PDGF-D-PDGFRβ signaling pathway is a mechanism by which IL-15 selectively regulates the survival of human NK cells without modulating their effector functions., Competing Interests: The authors declare no competing interest., (Copyright © 2022 the Author(s). Published by PNAS.)

Platelet-derived growth factor-D (PDGF-D) is highly expressed in immune cells. However, the potential role of PDGF-D in immune system remains thus far unclear. Here, we reveal a novel function of PDGF-D in activating both classical and alternative complement pathways that markedly increase chemokine and cytokine responses to promote macrophage polarization. Pharmacological targeting of the complement C3a receptor using SB290157 alleviated PDGF-D-induced neuroinflammation by blocking macrophage polarization and inhibited pathological choroidal neovascularization. Our study thus suggests that therapeutic strategies targeting both PDGF-D and the complement system may open up new possibilities for the treatment of neovascular diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation with the authors at the time of review., (Copyright © 2021 Xiong, Wang, Li, Huang, Zhang, Zhu, Xie, Wang, Kuang, Lin, Lee, Kumar and Li.)

Simple Summary: PDGF-D can be considered a candidate gene for selection for sheep tail type. This study investigated genetic variation of the PDGF-D gene in sheep with different tail types verified at a cellular level and revealed the molecular mechanism of PDGF-D in sheep tail fat deposition. We detected a total of two SNPs among 533 sheep. g.4122606 C > G site was significantly correlated with tail length, and g.3852134 C > T site was significantly correlated with tail width. In addition, overexpression of PDGF-D in sheep preadipocytes can promote adipogenic differentiation. The PDGF-D gene may participate in sheep tail fat deposition and could be used for molecular marker-assisted selection of sheep tail type. The aim of this study was to examine the correlation between the platelet-derived growth factor-D (PDGF-D) gene and sheep tail type character and explore the potential underlying mechanism. A total of 533 sheep were included in this study. Polymorphic sites were examined by Pool-seq, and individual genotype identification and correlation analysis between tail type data were conducted using the matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF-MS) method. JASPART website was used to predict transcription factor binding sites in the promoter region with and without PDGF-D gene mutation. The effect of PDGF-D on adipogenic differentiation of sheep preadipocytes was investigated. Two single nucleotide polymorphism sites were identified: g.4122606 C > G site was significantly correlated with tail length, and g.3852134 C > T site was significantly correlated with tail width. g.3852134 C > T was located in the promoter region. Six transcription factor binding sites were eliminated after promoter mutation, and three new transcription factor binding sites appeared. Expression levels of peroxisome proliferator-activated receptor gamma (PPARγ) and lipoproteinlipase (LPL) were significantly up-regulated upon PDGF-D overexpression. Oil red O staining showed increased small and large oil drops in the PDGF-D overexpression group. Together these results indicate the PDGF-D gene is an important gene controlling sheep tail shape and regulating sheep tail fat deposition to a certain degree. [ABSTRACT FROM AUTHOR]

Hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome is a life-threatening pregnancy complication. Though there are several medications widely used to treat HELLP syndrome, delivery is the only efficient treatment. The goal of the present study was to investigate the effects of platelet-derived growth factor-D (PDGF-D), a newly identified PDGF, in a rat model of HELLP syndrome which was accomplished by sFlt-1 and sEng injection. The expression levels of PDGF-D in pregnant women diagnosed with HELLP syndrome was determined. A HELLP rat model was established and the PDGF-D expression level in the plasma and the placenta tissue was evaluated. To evaluate the effects of PDGF-D in HELLP syndrome model, siPDGF-D was injected into the rats and the HELLP syndrome-related parameters were measured. The levels of inflammatory cytokines and PDGF-D were determined by ELISA. The oxidative stress activities in the plasma were also determined. Furthermore, the expression of PDGF-D/PDGFR-β/nuclear factor κB (NF-κB) p65 in placenta tissues was evaluated by Western blotting. Compared to the normal pregnant (NP) group, the levels of PDGF-D were augmented regardless of species. Knockdown of PDGF-D can result in the alleviation of HELLP syndrome development and progression in the HELLP rat model. Importantly, as a result of PDGF-D knockdown, the serum levels of inflammatory cytokines and oxidative stress activities were modulated, and the phosphorylation of PDGFR-β and NF-κB p65 in placenta tissue was inhibited. Taking together, our findings indicate that targeting PDGF-D could be used as a novel strategy to treat patients with HELLP syndrome.