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The Journal of Clinical Investigation Dec 2023Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel...
Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue is well studied, but microvascular calcification in the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular calcification in male mice. Aged male mice had higher serum PDGF-BB levels and a higher incidence of brain calcification compared with young mice, mainly in the thalamus. Transgenic mice with preosteoclast-specific Pdgfb overexpression exhibited elevated serum PDGF-BB levels and recapitulated age-associated thalamic calcification. Conversely, mice with preosteoclast-specific Pdgfb deletion displayed diminished age-associated thalamic calcification. In an ex vivo cerebral microvascular culture system, PDGF-BB dose-dependently promoted vascular calcification. Analysis of osteogenic gene array and single-cell RNA-Seq (scRNA-Seq) revealed that PDGF-BB upregulated multiple osteogenic differentiation genes and the phosphate transporter Slc20a1 in cerebral microvessels. Mechanistically, PDGF-BB stimulated the phosphorylation of its receptor PDGFRβ (p-PDGFRβ) and ERK (p-ERK), leading to the activation of RUNX2. This activation, in turn, induced the transcription of osteoblast differentiation genes in PCs and upregulated Slc20a1 in astrocytes. Thus, bone-derived PDGF-BB induced brain vascular calcification by activating the p-PDGFRβ/p-ERK/RUNX2 signaling cascade in cerebrovascular cells.
Topics: Animals; Male; Mice; Becaplermin; Brain; Core Binding Factor Alpha 1 Subunit; Osteogenesis; Proto-Oncogene Proteins c-sis; Receptor, Platelet-Derived Growth Factor beta; Vascular Calcification
PubMed: 37815871
DOI: 10.1172/JCI168447 -
Advanced Science (Weinheim,... Jul 2023Evidence suggests a unique association between bone aging and neurodegenerative/cerebrovascular disorders. However, the mechanisms underlying bone-brain interplay remain...
Evidence suggests a unique association between bone aging and neurodegenerative/cerebrovascular disorders. However, the mechanisms underlying bone-brain interplay remain elusive. Here platelet-derived growth factor-BB (PDGF-BB) produced by preosteoclasts in bone is reported to promote age-associated hippocampal vascular impairment. Aberrantly elevated circulating PDGF-BB in aged mice and high-fat diet (HFD)-challenged mice correlates with capillary reduction, pericyte loss, and increased blood-brain barrier (BBB) permeability in their hippocampus. Preosteoclast-specific Pdgfb transgenic mice with markedly high plasma PDGF-BB concentration faithfully recapitulate the age-associated hippocampal BBB impairment and cognitive decline. Conversely, preosteoclast-specific Pdgfb knockout mice have attenuated hippocampal BBB impairment in aged mice or HFD-challenged mice. Persistent exposure of brain pericytes to high concentrations of PDGF-BB upregulates matrix metalloproteinase 14 (MMP14), which promotes ectodomain shedding of PDGF receptor β (PDGFRβ) from pericyte surface. MMP inhibitor treatment alleviates hippocampal pericyte loss and capillary reduction in the conditional Pdgfb transgenic mice and antagonizes BBB leakage in aged mice. The findings establish the role of bone-derived PDGF-BB in mediating hippocampal BBB disruption and identify the ligand-induced PDGFRβ shedding as a feedback mechanism for age-associated PDGFRβ downregulation and the consequent pericyte loss.
Topics: Animals; Mice; Becaplermin; Hippocampus; Mice, Knockout; Mice, Transgenic; Pericytes; Proto-Oncogene Proteins c-sis; Receptor, Platelet-Derived Growth Factor beta
PubMed: 37102631
DOI: 10.1002/advs.202206938 -
Journal of Molecular Medicine (Berlin,... Mar 2013Retinal and choroidal vascular diseases constitute the most common causes of moderate and severe vision loss in developed countries. They can be divided into retinal... (Review)
Review
Retinal and choroidal vascular diseases constitute the most common causes of moderate and severe vision loss in developed countries. They can be divided into retinal vascular diseases, in which there is leakage and/or neovascularization (NV) from retinal vessels, and subretinal NV, in which new vessels grow into the normally avascular outer retina and subretinal space. The first category of diseases includes diabetic retinopathy, retinal vein occlusions, and retinopathy of prematurity, and the second category includes neovascular age-related macular degeneration (AMD), ocular histoplasmosis, pathologic myopia, and other related diseases. Retinal hypoxia is a key feature of the first category of diseases resulting in elevated levels of hypoxia-inducible factor-1 (HIF-1) which stimulates expression of vascular endothelial growth factor (VEGF), platelet-derived growth factor-B (PDGF-B), placental growth factor, stromal-derived growth factor-1 and their receptors, as well as other hypoxia-regulated gene products such as angiopoietin-2. Although hypoxia has not been demonstrated as part of the second category of diseases, HIF-1 is elevated and thus the same group of hypoxia-regulated gene products plays a role. Clinical trials have shown that VEGF antagonists provide major benefits for patients with subretinal NV due to AMD and even greater benefits are seen by combining antagonists of VEGF and PDGF-B. It is likely that addition of antagonists of other agents listed above will be tested in the future. Other appealing strategies are to directly target HIF-1 or to use gene transfer to express endogenous or engineered anti-angiogenic proteins. While substantial progress has been made, the future looks even brighter for patients with retinal and choroidal vascular diseases.
Topics: Angiopoietin-2; Becaplermin; Choroidal Neovascularization; Clinical Trials as Topic; Eye; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Macular Degeneration; Proto-Oncogene Proteins c-sis; Retinal Neovascularization; Retinal Vessels; Vascular Endothelial Growth Factor A
PubMed: 23329331
DOI: 10.1007/s00109-013-0993-5 -
The Journal of Clinical Investigation Oct 2021Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth...
Evidence links osteoporosis and cardiovascular disease but the cellular and molecular mechanisms are unclear. Here we identify skeleton-secreted platelet-derived growth factor-BB (PDGF-BB) as a key mediator of arterial stiffening in response to aging and metabolic stress. Aged mice and those fed high-fat diet (HFD), relative to young mice and those fed normal chow food diet, respectively, had higher serum PDGF-BB and developed bone loss and arterial stiffening. Bone/bone marrow preosteoclasts in aged mice and HFD mice secrete an excessive amount of PDGF-BB, contributing to the elevated PDGF-BB in blood circulation. Conditioned medium prepared from preosteoclasts stimulated proliferation and migration of the vascular smooth muscle cells. Conditional transgenic mice, in which PDGF-BB is overexpressed in preosteoclasts, had 3-fold higher serum PDGF-BB concentration and developed simultaneous bone loss and arterial stiffening spontaneously at a young age. Conversely, in conditional knockout mice, in which PDGF-BB is deleted selectively in preosteoclasts, HFD did not affect serum PDGF-BB concentration; as a result, HFD-induced bone loss and arterial stiffening were attenuated. These studies confirm that preosteoclasts are a main source of excessive PDGF-BB in blood circulation during aging and metabolic stress and establish the role of skeleton-derived PDGF-BB as an important mediator of vascular stiffening.
Topics: Aging; Animals; Becaplermin; Bone Resorption; Diet, High-Fat; Humans; Male; Mice; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Osteoclasts; Rats; Rats, Sprague-Dawley; Vascular Stiffness
PubMed: 34437300
DOI: 10.1172/JCI147116 -
Clinical and Experimental Hypertension... Dec 2023Neointimal hyperplasia is the primary mechanism underlying atherosclerosis and restenosis after percutaneous coronary intervention. Ketogenic diet (KD) exerts beneficial...
OBJECTIVE
Neointimal hyperplasia is the primary mechanism underlying atherosclerosis and restenosis after percutaneous coronary intervention. Ketogenic diet (KD) exerts beneficial effects in various diseases, but whether it could serve as non-drug therapy for neointimal hyperplasia remains unknown. This study aimed to investigate the effect of KD on neointimal hyperplasia and the potential mechanisms.
METHODS AND RESULTS
Carotid artery balloon-injury model was employed in adult Sprague-Dawley rats to induce neointimal hyperplasia. Then, animals were subjected to either standard rodent chow or KD. For in-vitro experiment, impacts of β-hydroxybutyrate (β-HB), the main mediator of KD effects, on platelet-derived growth factor BB (PDGF-BB) induced vascular smooth muscle cell (VSMC) migration and proliferation were determined. Balloon injury induced event intimal hyperplasia and upregulation of protein expression of proliferating cell nuclear antigen (PCNA) and α-smooth muscle actin (α-SMA), and these changes were significantly ameliorated by KD. In addition, β-HB could markedly inhibit PDGF-BB induced VMSC migration and proliferation, as well as inhibiting expressions of PCNA and α-SMC. Furthermore, KD inhibited balloon-injury induced oxidative stress in carotid artery, indicated by reduced ROS level, malondialdehyde (MDA) and myeloperoxidase (MPO) activities, and increased superoxide dismutase (SOD) activity. We also found balloon-injury induced inflammation in carotid artery was suppressed by KD, indicated by decreased expressions of proinflammatory cytokines IL-1β and TNF-α, and increased expression of anti-inflammatory cytokine IL-10.
CONCLUSION
KD attenuates neointimal hyperplasia through suppressing oxidative stress and inflammation to inhibit VSMC proliferation and migration. KD may represent a promising non-drug therapy for neointimal hyperplasia associated diseases.
Topics: Rats; Animals; Hyperplasia; Rats, Sprague-Dawley; Becaplermin; Proliferating Cell Nuclear Antigen; Diet, Ketogenic; Neointima; Carotid Artery Injuries; Oxidative Stress; Inflammation; Cell Proliferation; Cell Movement; Cells, Cultured
PubMed: 37395230
DOI: 10.1080/10641963.2023.2229538 -
Scientific Reports Sep 2023The heart depends on a functional vasculature for oxygenation and transport of nutrients, and it is of interest to learn how primary impairment of the vasculature can...
The heart depends on a functional vasculature for oxygenation and transport of nutrients, and it is of interest to learn how primary impairment of the vasculature can indirectly affect cardiac function and heart morphology. Notch3-deficiency causes vascular smooth muscle cell (VSMC) loss in the vasculature but the consequences for the heart remain largely elusive. Here, we demonstrate that Notch3 mice have enlarged hearts with left ventricular hypertrophy and mild fibrosis. Cardiomyocytes were hypertrophic but not hyperproliferative, and the expression of several cardiomyocyte markers, including Tnt2, Myh6, Myh7 and Actn2, was altered. Furthermore, expression of genes regulating the metabolic status of the heart was affected: both Pdk4 and Cd36 were downregulated, indicating a metabolic switch from fatty acid oxidation to glucose consumption. Notch3 mice furthermore showed lower liver lipid content. Notch3 was expressed in heart VSMC and pericytes but not in cardiomyocytes, suggesting that a perturbation of Notch signalling in VSMC and pericytes indirectly impairs the cardiomyocytes. In keeping with this, Pdgfb mice, characterized by reduced numbers of VSMC and pericytes, showed left ventricular and cardiomyocyte hypertrophy. In conclusion, we demonstrate that reduced Notch3 or PDGFB signalling in vascular mural cells leads to cardiomyocyte dysfunction.
Topics: Animals; Mice; Becaplermin; Cardiomegaly; Hypertrophy, Left Ventricular; Lipid Metabolism; Myocytes, Cardiac; Proto-Oncogene Proteins c-sis
PubMed: 37699967
DOI: 10.1038/s41598-023-42010-7 -
Biomolecules Oct 2022Tendon injuries are one of the most common musculoskeletal disorders for which patients seek medical aid, reducing not only the quality of life of the patient but also... (Review)
Review
Tendon injuries are one of the most common musculoskeletal disorders for which patients seek medical aid, reducing not only the quality of life of the patient but also imposing a significant economic burden on society. The administration of growth factors at the wound site is a feasible solution for enhancing tendon healing. Platelet-derived growth factor-BB (PDGF-BB) has a well-defined safety profile compared to other growth factors and has been approved by the Food and Drug Administration (FDA). The purpose of this review is to summarize the role of PDGF-BB in tendon healing through a comprehensive review of the published literature. Experimental studies suggest that PDGF-BB has a positive effect on tendon healing by enhancing inflammatory responses, speeding up angiogenesis, stimulating tendon cell proliferation, increasing collagen synthesis and increasing the biomechanics of the repaired tendon. PDGF-BB is regarded as a promising candidate in tendon healing. However, in order to realize its full potential, we still need to carefully consider and study key issues such as dose and application time in the future, so as to explore further applications of PDGF-BB in the tendon healing process.
Topics: United States; Humans; Becaplermin; Proto-Oncogene Proteins c-sis; Quality of Life; Tendons; Collagen
PubMed: 36291727
DOI: 10.3390/biom12101518 -
The Journal of Clinical Investigation Nov 2023Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of...
Glioblastoma (GBM) tumor-associated macrophages (TAMs) provide a major immune cell population contributing to growth and immunosuppression via the production of proinflammatory factors, including IL-1. In this issue of the JCI, Chen, Giotti, and colleagues investigated loss of ll1b in the immune tumor microenvironment (TME) in GBM models driven by PDGFB expression and Nf1 knockdown. Survival was only improved in PDGFB-driven GBM models, suggesting that tumor cell genotype influenced the immune TME. IL-1β in the TME increased PDGFB-driven GBM growth by increasing tumor-derived NF-κB, expression of monocyte chemoattractants, and increased infiltration of bone marrow-derived myeloid cells (BMDMs). In contrast, no requirement for IL-1β was evident in Nf1-silenced tumors due to high basal levels of NF-κB and monocyte chemoattractants and increased infiltration of BMDM and TAMs. Notably, treatment of mice bearing PDGFB-driven GBM with anti-IL-1β or an IL1R1 antagonist extended survival. These findings suggest that effective clinical immunotherapy may require differential targeting strategies.
Topics: Animals; Mice; Becaplermin; Brain Neoplasms; Chemotactic Factors; Cytokines; Glioblastoma; Macrophages; NF-kappa B; Proto-Oncogene Proteins c-sis; Tumor Microenvironment
PubMed: 37966120
DOI: 10.1172/JCI175127 -
International Journal of Molecular... Oct 2023Since the only and the milestone FDA approval of becaplermin gel (Regranex, 0.01% human recombinant PDGF-BB) as a (diabetic) wound healing therapeutic more than 25 years... (Review)
Review
Since the only and the milestone FDA approval of becaplermin gel (Regranex, 0.01% human recombinant PDGF-BB) as a (diabetic) wound healing therapeutic more than 25 years ago, no new therapeutic (excluding physical therapies, devices, dressings, anti-microbial agents, or other preventive treatments) for any type of wound healing has advanced to clinical applications. During the same period of time, the FDA has approved additional 250 new drugs for various human tumors, which were famously described as "wounds that do not heal". Two similar pathological conditions have experienced such a dramatic difference in therapeutics. More surprisingly, few in the wound healing community seem to be alarmed by this mysterious deficit. As it is often said, "damaging is far easier than re-building". In contrast to the primary duty of a cancer drug to damage a single molecule of the signaling network, a wound healing drug must be able to re-build the multi-level damages in the wound. No known single molecule alone is capable of repairing multi-cell-type and multi-pathway damages all at once. We argue that the previous single molecule-based strategy for developing wound healing therapeutics is profoundly flawed in theory. The future success of effective wound healing therapeutics requires a fundamental change in the paradigm.
Topics: Humans; Proto-Oncogene Proteins c-sis; Wound Healing; Becaplermin; Bandages
PubMed: 37894789
DOI: 10.3390/ijms242015109 -
BioMed Research International 2015The advancement of molecular mediators or biologic agents has increased tremendously during the last decade in periodontology and dental implantology. Implant site... (Review)
Review
The advancement of molecular mediators or biologic agents has increased tremendously during the last decade in periodontology and dental implantology. Implant site development and reconstruction of the lost periodontium represent main fields in which these molecular mediators have been employed and investigated. Different growth factors trigger different reactions in the tissues of the periodontium at various cellular levels. Proliferation, migration, and differentiation constitute the main target areas of these molecular mediators. It was the purpose of this comprehensive review to describe the origin and rationale, evidence, and the most current understanding of the following biologic agents: Recombinant Human Platelet-Derived Growth Factor-BB (rhPDGF-BB), Enamel Matrix Derivate (EMD), Platelet-Rich Plasma (PRP) and Platelet-Rich Fibrin (PRF), Recombinant Human Fibroblast Growth Factor-2 (rhFGF-2), Bone Morphogenic Proteins (BMPs, BMP-2 and BMP-7), Teriparatide PTH, and Growth Differential Factor-5 (GDF-5).
Topics: Becaplermin; Bone Morphogenetic Proteins; Dental Enamel Proteins; Dental Implants; Growth Differentiation Factor 5; Guided Tissue Regeneration, Periodontal; Humans; Periodontium; Platelet-Rich Plasma; Proto-Oncogene Proteins c-sis; Recombinant Proteins
PubMed: 26509173
DOI: 10.1155/2015/957518