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Circulation Research Oct 2022Phenotypic transition of vascular smooth muscle cells (VSMCs) accounts for the pathogenesis of a variety of vascular diseases during the early stage. Recent studies...
BACKGROUND
Phenotypic transition of vascular smooth muscle cells (VSMCs) accounts for the pathogenesis of a variety of vascular diseases during the early stage. Recent studies indicate the metabolic reprogramming may be involved in VSMC phenotypic transition. However, the definite molecules that link energy metabolism to distinct VSMC phenotype remain elusive.
METHODS
A carotid artery injury model was used to study postinjury neointima formation as well as VSMC phenotypic transition in vivo. RNA-seq analysis, cell migration assay, collagen gel contraction assay, wire myography assay, immunoblotting, protein interactome analysis, co-immunoprecipitation, and mammalian 2-hybrid assay were performed to clarify the phenotype and elucidate the molecular mechanisms.
RESULTS
We collected cell energy-regulating genes by using Gene Ontology annotation and applied RNA-Seq analysis of transforming growth factor-β or platelet-derived growth factor BB stimulated VSMCs. Six candidate genes were overlapped from energy metabolism-related genes and genes reciprocally upregulated by transforming growth factor-β and downregulated by platelet-derived growth factor BB. Among them, prohibitin 2 has been reported to regulate mitochondrial oxidative phosphorylation. Indeed, prohibitin 2-deficient VSMCs lost the contractile phenotype as evidenced by reduced contractile proteins. Consistently, mice were more susceptible to postinjury VSMC proliferation and neointima formation compared with mice. Further protein interactome analysis, co-immunoprecipitation, and mammalian 2-hybrid assay revealed that prohibitin 2, through its C-terminus, directly interacts with hnRNPA1, a key modulator of pyruvate kinase M1/2 (PKM) mRNA splicing that promotes PKM2 expression and glycolysis. Prohibitin 2 deficiency facilitated PKM1/2 mRNA splicing and reversion from PKM1 to PKM2, and enhanced glycolysis in VSMCs. Blocking prohibitin 2-hnRNPA1 interaction resulted in increased PKM2 expression, enhanced glycolysis, repressed contractile marker genes expression in VSMCs, as well as aggravated postinjury neointima formation in vivo.
CONCLUSIONS
Prohibitin 2 maintains VSMC contractile phenotype by interacting with hnRNPA1 to counteract hnRNPA1-mediated PKM alternative splicing and glucose metabolic reprogramming.
Topics: Animals; Mice; Becaplermin; Cell Movement; Cell Proliferation; Cells, Cultured; Mammals; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima; Phenotype; RNA, Messenger; Transforming Growth Factors; Prohibitins
PubMed: 36200440
DOI: 10.1161/CIRCRESAHA.122.321005 -
Nature Cell Biology Aug 2015The use of human pluripotent stem cells for in vitro disease modelling and clinical applications requires protocols that convert these cells into relevant adult cell...
The use of human pluripotent stem cells for in vitro disease modelling and clinical applications requires protocols that convert these cells into relevant adult cell types. Here, we report the rapid and efficient differentiation of human pluripotent stem cells into vascular endothelial and smooth muscle cells. We found that GSK3 inhibition and BMP4 treatment rapidly committed pluripotent cells to a mesodermal fate and subsequent exposure to VEGF-A or PDGF-BB resulted in the differentiation of either endothelial or vascular smooth muscle cells, respectively. Both protocols produced mature cells with efficiencies exceeding 80% within six days. On purification to 99% via surface markers, endothelial cells maintained their identity, as assessed by marker gene expression, and showed relevant in vitro and in vivo functionality. Global transcriptional and metabolomic analyses confirmed that the cells closely resembled their in vivo counterparts. Our results suggest that these cells could be used to faithfully model human disease.
Topics: Animals; Becaplermin; Biomarkers; Bone Morphogenetic Protein 4; Cell Differentiation; Cell Line; Cell Lineage; Coculture Techniques; Dose-Response Relationship, Drug; Endothelial Cells; Gene Expression Profiling; Gene Expression Regulation, Developmental; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Human Umbilical Vein Endothelial Cells; Humans; Induced Pluripotent Stem Cells; Metabolomics; Mice, Inbred NOD; Mice, SCID; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neovascularization, Physiologic; Phenotype; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-sis; Time Factors; Transcription, Genetic; Transfection; Vascular Endothelial Growth Factor A; Wnt Signaling Pathway
PubMed: 26214132
DOI: 10.1038/ncb3205 -
Nature Medicine Nov 2014Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and...
Osteogenesis during bone modeling and remodeling is coupled with angiogenesis. A recent study showed that a specific vessel subtype, strongly positive for CD31 and endomucin (CD31(hi)Emcn(hi)), couples angiogenesis and osteogenesis. Here, we found that platelet-derived growth factor-BB (PDGF-BB) secreted by preosteoclasts induces CD31(hi)Emcn(hi) vessel formation during bone modeling and remodeling. Mice with depletion of PDGF-BB in the tartrate-resistant acid phosphatase-positive cell lineage show significantly lower trabecular and cortical bone mass, serum and bone marrow PDGF-BB concentrations, and fewer CD31(hi)Emcn(hi) vessels compared to wild-type mice. In the ovariectomy (OVX)-induced osteoporotic mouse model, serum and bone marrow levels of PDGF-BB and numbers of CD31(hi)Emcn(hi) vessels are significantly lower compared to sham-operated controls. Treatment with exogenous PDGF-BB or inhibition of cathepsin K to increase the number of preosteoclasts, and thus the endogenous levels of PDGF-BB, increases CD31(hi)Emcn(hi) vessel number and stimulates bone formation in OVX mice. Thus, pharmacotherapies that increase PDGF-BB secretion from preosteoclasts offer a new therapeutic target for treating osteoporosis by promoting angiogenesis and thus bone formation.
Topics: Acid Phosphatase; Animals; Becaplermin; Cathepsin K; Cell Count; Cell Movement; Culture Media, Conditioned; Endothelial Cells; Female; Femur; Focal Adhesion Protein-Tyrosine Kinases; Isoenzymes; Mesenchymal Stem Cells; Mice, Inbred C57BL; Neovascularization, Physiologic; Osteoclasts; Osteogenesis; Ovariectomy; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1; Protease Inhibitors; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-sis; Tartrate-Resistant Acid Phosphatase; X-Ray Microtomography
PubMed: 25282358
DOI: 10.1038/nm.3668 -
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 -
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 -
Journal of Periodontology Dec 2022The use of biologics may be indicated for alveolar ridge preservation (ARP) and reconstruction (ARR), and implant site development (ISD). The present systematic review...
BACKGROUND
The use of biologics may be indicated for alveolar ridge preservation (ARP) and reconstruction (ARR), and implant site development (ISD). The present systematic review aimed to analyze the effect of autologous blood-derived products (ABPs), enamel matrix derivative (EMD), recombinant human platelet-derived growth factor-BB (rhPDGF-BB), and recombinant human bone morphogenetic protein-2 (rhBMP-2), on the outcomes of ARP/ARR and ISD therapy (i.e., alveolar ridge augmentation [ARA] and maxillary sinus floor augmentation [MSFA]).
METHODS
An electronic search for eligible articles published from January 2000 to October 2021 was conducted. Randomized clinical trials evaluating the efficacy of ABPs, EMD, rhBMP-2, and rhPDGF-BB for ARP/ARR and ISD were included according to pre-established eligibility criteria. Data on linear and volumetric dimensional changes, histomorphometric findings, and a variety of secondary outcomes (i.e., clinical, implant-related, digital imaging, safety, and patient-reported outcome measures [PROMs]) were extracted and critically analyzed. Risk of bias assessment of the selected investigations was also conducted.
RESULTS
A total of 39 articles were included and analyzed qualitatively. Due to the high level of heterogeneity across studies, quantitative analyses were not feasible. Most studies in the topic of ARP/ARR revealed that the use of biologics rendered similar results compared with conventional protocols. However, when juxtaposed to unassisted healing or socket filling using collagen sponges, the application of biologics did contribute to attenuate post-extraction alveolar ridge atrophy in most investigations. Additionally, histomorphometric outcomes were positively influenced by the application of biologics. The use of biologics in ARA interventions did not yield superior clinical or radiographic outcomes compared with control therapies. Nevertheless, ABPs enhanced new bone formation and reduced the likelihood of early wound dehiscence. The use of biologics in MSFA interventions did not translate into superior clinical or radiographic outcomes. It was observed, though, that the use of some biologics may promote bone formation during earlier stages of healing. Only four clinical investigations evaluated PROMs and reported a modest beneficial impact of the use of biologics on pain and swelling. No severe adverse events in association with the use of the biologics evaluated in this systematic review were noted.
CONCLUSIONS
Outcomes of therapy after post-extraction ARP/ARR and ARA in edentulous ridges were comparable among different therapeutic modalities evaluated in this systematic review. Nevertheless, the use of biologics (i.e., PRF, EMD, rhPDGF-BB, and rhBMP-2) in combination with a bone graft material generally results into superior histomorphometric outcomes and faster wound healing compared with control groups.
Topics: Humans; Tooth Socket; Sinus Floor Augmentation; Biological Products; Becaplermin; Alveolar Ridge Augmentation; Alveolar Process; Tooth Extraction
PubMed: 35841608
DOI: 10.1002/JPER.22-0069 -
JCI Insight Apr 2020Increased subchondral bone angiogenesis with blood vessels breaching the tidemark into the avascular cartilage is a diagnostic feature of human osteoarthritis. However,...
Increased subchondral bone angiogenesis with blood vessels breaching the tidemark into the avascular cartilage is a diagnostic feature of human osteoarthritis. However, the mechanisms that initiate subchondral bone angiogenesis remain unclear. We show that abnormally increased platelet-derived growth factor-BB (PDGF-BB) secretion by mononuclear preosteoclasts induces subchondral bone angiogenesis, contributing to osteoarthritis development. In mice after destabilization of the medial meniscus (DMM), aberrant joint subchondral bone angiogenesis developed during an early stage of osteoarthritis, before articular cartilage damage occurred. Mononuclear preosteoclasts in subchondral bone secrete excessive amounts of PDGF-BB, which activates platelet-derived growth factor receptor-β (PDGFR-β) signaling in pericytes for neo-vessel formation. Selective knockout of PDGF-BB in preosteoclasts attenuates subchondral bone angiogenesis and abrogates joint degeneration and subchondral innervation induced by DMM. Transgenic mice that express PDGF-BB in preosteoclasts recapitulate pathological subchondral bone angiogenesis and develop joint degeneration and subchondral innervation spontaneously. Our study provides the first evidence to our knowledge that PDGF-BB derived from preosteoclasts is a key driver of pathological subchondral bone angiogenesis during osteoarthritis development and offers a new avenue for developing early treatments for this disease.
Topics: Animals; Becaplermin; Bone and Bones; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Osteoarthritis; Osteoclasts
PubMed: 32208385
DOI: 10.1172/jci.insight.135446 -
Redox Biology Apr 2018Phenotypic switch of vascular smooth muscle cells (VSMCs) is characterized by increased expressions of VSMC synthetic markers and decreased levels of VSMC contractile...
Phenotypic switch of vascular smooth muscle cells (VSMCs) is characterized by increased expressions of VSMC synthetic markers and decreased levels of VSMC contractile markers, which is an important step for VSMC proliferation and migration during the development and progression of cardiovascular diseases including atherosclerosis. Chicoric acid (CA) is identified to exert powerful cardiovascular protective effects. However, little is known about the effects of CA on VSMC biology. Herein, in cultured VSMCs, we showed that pretreatment with CA dose-dependently suppressed platelet-derived growth factor type BB (PDGF-BB)-induced VSMC phenotypic alteration, proliferation and migration. Mechanistically, PDGF-BB-treated VSMCs exhibited higher mammalian target of rapamycin (mTOR) and P70S6K phosphorylation, which was attenuated by CA pretreatment, diphenyleneiodonium chloride (DPI), reactive oxygen species (ROS) scavenger N-acetyl-l-cysteine (NAC) and nuclear factor-κB (NFκB) inhibitor Bay117082. PDGF-BB-triggered ROS production and p65-NFκB activation were inhibited by CA. In addition, both NAC and DPI abolished PDGF-BB-evoked p65-NFκB nuclear translocation, phosphorylation and degradation of Inhibitor κBα (IκBα). Of note, blockade of ROS/NFκB/mTOR/P70S6K signaling cascade prevented PDGF-BB-evoked VSMC phenotypic transformation, proliferation and migration. CA treatment prevented intimal hyperplasia and vascular remodeling in rat models of carotid artery ligation in vivo. These results suggest that CA impedes PDGF-BB-induced VSMC phenotypic switching, proliferation, migration and neointima formation via inhibition of ROS/NFκB/mTOR/P70S6K signaling cascade.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Becaplermin; Caffeic Acids; Cell Dedifferentiation; Cell Line; Cell Movement; Cell Proliferation; Humans; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Proto-Oncogene Proteins c-sis; Rats, Sprague-Dawley; Reactive Oxygen Species; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Succinates; TOR Serine-Threonine Kinases
PubMed: 29175753
DOI: 10.1016/j.redox.2017.11.012 -
Advanced Science (Weinheim,... Aug 2023Hippocampal circuitry stimulation is sufficient to regulate adult hippocampal neurogenesis and ameliorate depressive-like behavior, but its underlying mechanism remains...
Hippocampal circuitry stimulation is sufficient to regulate adult hippocampal neurogenesis and ameliorate depressive-like behavior, but its underlying mechanism remains unclear. Here, it is shown that inhibition of medial septum (MS)-dentate gyrus (DG) circuit reverses the chronic social defeat stress (CSDS)-induced depression-like behavior. Further analysis exhibits that inhibition of gamma-aminobutyric acidergic neurons in MS projecting to the DG (MS -DG) increases the expression of platelet-derived growth factor-BB (PDGF-BB) in somatostatin (SOM) positive interneurons of DG, which contributes to the antidepressant-like effects. Overexpression of the PDGF-BB or exogenous administration of PDGF-BB in DG rescues the effect of chronic stress on the inhibition of neural stem cells (NSCs) proliferation and dendritic growth of adult-born hippocampal neurons, as well as on depressive-like behaviors. Conversely, knockdown of PDGF-BB facilitates CSDS-induced deficit of hippocampal neurogenesis and promotes the susceptibility to chronic stress in mice. Finally, conditional knockdown platelet-derived growth factor receptor beta (PDGFRβ) in NSCs blocks an increase in NSCs proliferation and the antidepressant effects of PDGF-BB. These results delineate a previously unidentified PDGF-BB/PDGFRβ signaling in regulating depressive-like behaviors and identify a novel mechanism by which the MS -DG pathway regulates the expression of PDGF-BB in SOM-positive interneurons.
Topics: Mice; Animals; Becaplermin; Neurogenesis; gamma-Aminobutyric Acid; Antidepressive Agents; Dentate Gyrus
PubMed: 37325895
DOI: 10.1002/advs.202301110 -
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