• CP: Cell biology
• CP: Stem cell research
• NO
• SPCs
• bio-hybrid vascular graft
• nitric oxide
• vascular calcification
• vascular stem/progenitor cells

• Animals
• Disease Models, Animal
• Humans
• Hyperplasia/etiology
• Mice
• Nitric Oxide
• Rabbits
• Spinocerebellar Ataxias
• Stem Cells
• Swine
• Vascular Grafting/adverse effects

Artificial small-diameter vascular grafts (SDVG) fabricated from synthetic biodegradable polymers, such as poly(ε-caprolactone) (PCL), exhibit beneficial mechanical properties but are often faced with issues impacting their long-term graft success. Nitric oxide (NO) is an important physiological gasotransmitter with multiple roles in orchestrating vascular tissue function and regeneration. We fabricated a functional vascular graft by electrospinning of nitrate-functionalized poly(ε-caprolactone) that could release NO in a sustained manner via stepwise biotransformation in vivo. Nitrate-functionalized SDVG (PCL/NO) maintained patency following abdominal arterial replacement in rats. PCL/NO promoted cell infiltration at 3-months post-transplantation. In contrast, unmodified PCL SDVG showed slow cell in-growth and increased incidence of neointima formation. PCL/NO demonstrated improved endothelial cell (EC) alignment and luminal coverage, and more defined vascular smooth muscle cell (VSMC) layer, compared to unmodified PCL SDVG. In addition, release of NO stimulated Sca-1⁺ vascular progenitor cells (VPCs) to differentiate and contribute to rapid luminal endothelialization. Furthermore, PCL/NO inhibited the differentiation of VPCs into osteopontin-positive cells, thereby preventing vascular calcification. Overall, PCL/NO demonstrated enhanced cell ingrowth, EC monolayer formation and VSMC layer regeneration; whilst inhibiting calcified plaque formation. Our results suggested that PCL/NO could serve as promising candidates for improved and long-term success of SDVG implants.

• nitric oxide
• small-diameter vascular grafts
• vascular calcification
• vascular progenitor cells (VPCs)
• vascular regeneration

Vascular calcification increases morbidity and mortality in patients with cardiovascular and renal diseases. Previously, we reported that histone deacetylase 1 prevents vascular calcification, whereas its E3 ligase, mouse double minute 2 homolog (MDM2), induces vascular calcification. In the present study, we identified the upstream regulator of MDM2. By utilizing cellular models and transgenic mice, we confirmed that E3 ligase activity is required for vascular calcification. By promoter analysis, we found that both msh homeobox 1 (Msx1) and msh homeobox 2 (Msx2) bound to the MDM2 promoter region, which resulted in transcriptional activation of MDM2. The expression levels of both Msx1 and Msx2 were increased in mouse models of vascular calcification and in calcified human coronary arteries. Msx1 and Msx2 potentiated vascular calcification in cellular and mouse models in an MDM2-dependent manner. Our results establish a novel role for MSX1/MSX2 in the transcriptional activation of MDM2 and the resultant increase in MDM2 E3 ligase activity during vascular calcification.

The identification of a signaling pathway involved in triggering vascular calcification, the deposition of calcium phosphate crystals in blood vessels, could inform new therapeutic interventions for related cardiovascular complications. Vascular calcification causes significant complications in patients with metabolic syndrome, renal failure, or cardiovascular disease. In their previous work, Hyun Kook and Duk-Hwa Kwon at Chonnam National University Medical School, Jeollanamdo, Republic of Korea, and coworkers demonstrated that the E3 ligase activity of a protein called MDM2 induces calcification. Now, following further mouse trials, the team have identified an upstream signaling pathway involving several development proteins such as MSX1 and MSX2 which activate MDM2. The activation of this signaling axis leads to the degradation of a key protein that would otherwise prevent calcification. The results may provide a platform for novel therapies targeting the condition.

Atherosclerotic vascular calcification contributes to increased risk of death in patients with cardiovascular diseases. Assessing the type and severity of inflammation is crucial in the treatment of numerous cardiovascular conditions. IL-1β, a potent proinflammatory cytokine, plays diverse roles in the pathogenesis of atherosclerotic vascular calcification. Several large-scale, population cohort trials have shown that the incidence of cardiovascular events is clinically reduced by the administration of anti-IL-1β therapy. Anti-IL-1β therapy might reduce the incidence of cardiovascular events by affecting atherosclerotic vascular calcification, but the mechanism underlying this effect remains unclear. In this review, we summarize current knowledge on the role of IL-1β in atherosclerotic vascular calcification, and describe the latest results reported in clinical trials evaluating anti-IL-1β therapies for the treatment of cardiovascular diseases. This review will aid in improving current understanding of the pathophysiological roles of IL-1β and mechanisms underlying its activity.

• IL-1β
• cardiovascular events
• signaling pathways
• vascular calcification

• CDC42
• Meox1
• Neointima
• SDF-1α
• Sca-1

Arterial calcification refers to the abnormal deposition of calcium salts in the arterial wall, which results in vessel lumen stenosis and vascular remodeling. Studies increasingly show that arterial calcification is a cell mediated, reversible and active regulated process similar to physiological bone mineralization. The osteoblasts and chondrocytes-like cells are present in large numbers in the calcified lesions, and express osteogenic transcription factor and bone matrix proteins that are known to initiate and promote arterial calcification. In addition, osteoclast-like cells have also been detected in calcified arterial walls wherein they possibly inhibit vascular calcification, similar to the catabolic process of bone mineral resorption. Therefore, tilting the balance between osteoblast-like and osteoclast-like cells to the latter maybe a promising therapeutic strategy against vascular calcification. In this review, we have summarized the current findings on the origin and functions of osteoblast-like and osteoclast-like cells in the development and progression of vascular progression, and explored novel therapeutic possibilities.

• cell therapy
• origin
• osteoblast-like cells
• osteoclast-like cells
• reversibe
• vascular calcification

• Brainbow
• RNA sequencing
• fibrosis
• hindlimb ischemia
• platelet-derived growth factor receptor α
• regeneration
• revascularization

As the most important component of the vascular wall, vascular smooth muscle cells (VSMCs) participate in the pathological process by phenotype transformation or differentiation from stem/progenitor cells. The main purpose of this study was to reveal the role and related molecular mechanism of microRNA-30c-5p (miR-30c-5p) in VSMC differentiation from adventitial progenitor cells expressing stem cell antigen-1(Sca-1).

In this study, we detected the expression of miR-30c-5p in human normal peripheral arteries and atherosclerotic arteries. In vitro, a stable differentiation model from adventitial Sca-1⁺ progenitor cells to VSMCs was established using transforming growth factor-β1 (TGF-β1) induction and the expression of miR-30c-5p during the process was observed. Then, we explored the effect of miR-30c-5p overexpression and inhibition on the differentiation from adventitial Sca-1⁺ progenitor cells to VSMCs. The target genes of miR-30c-5p were identified by protein chip and biological analyses and the expression of these genes in the differentiation process were detected. Further, the relationship between the target gene and miR-30c-5p and its effect on differentiation were evaluated. Finally, the co-transfection of miR-30c-5p inhibitor and small interfering RNA (siRNA) of the target gene was implemented to verify the functional target gene of miR-30c-5p during the differentiation from adventitial Sca-1⁺ progenitor cells to VSMCs, and the dual-luciferase reporter gene assay was performed to detect whether the mRNA 3′untranslated region (UTR) of the target gene is the direct binding site of miR-30c-5p.

The expression of miR-30c-5p in the human atherosclerotic arteries was significantly lower than that in the normal arteries. During the differentiation from adventitial Sca-1⁺ progenitor cells to VSMCs, the expression of VSMC special markers including smooth muscle α-actin (SMαA), smooth muscle-22α (SM22α), smooth muscle myosin heavy chain (SMMHC), and h1-caponin increased accompanied with cell morphology changing from elliptic to fusiform. Meanwhile, the expression of miR-30c-5p decreased significantly. In functional experiments, overexpression of miR-30c-5p inhibited SMαA, SM22α, SMMHC, and h1-caponin at the mRNA and protein levels. In contrast, inhibition of miR-30c-5p promoted the expression of SMαA, SM22α, SMMHC, and h1-caponin. The target gene, osteoprotegerin (OPG), was predicted through protein chip and bioinformatics analyses. Overexpression of miR-30c-5p inhibited OPG expression while inhibition of miR-30c-5p had an opposite effect. Co-transfection experiments showed that low expression of OPG could weaken the promotion effect of miR-30c-5p inhibitor on the differentiation from adventitial Sca-1⁺ progenitor cells to VSMCs and the dual-luciferase reporter gene assay demonstrated that miR-30c-5p could target the mRNA 3′UTR of OPG directly.

This study demonstrates that miR-30c-5p expression was significantly decreased in atherosclerotic arteries and miR-30c-5p inhibited VSMC differentiation from adventitial Sca-1⁺ progenitor cells through targeting OPG, which may provide a new target for the treatment of VSMCs-associated diseases.

• Differentiation
• MiR-30c-5p
• OPG
• Vascular progenitor cells
• Vascular smooth muscle cells

• Arterial calcification
• Clinical implication
• Pathobiology
• Therapeutic strategy

• adipose stem cell
• adventicyte
• adventitial cell
• mesenchymal stem cell
• pericyte
• perivascular stem cell

Accumulation of vascular smooth muscle cells (VSMCs) within the neointimal region is a hallmark of atherosclerosis and vessel injury. Evidence has shown that Sca-1-positive (Sca-1+) progenitor cells residing in the vascular adventitia play a crucial role in VSMC assemblages and intimal lesions. However, the underlying mechanisms, especially in the circumstances of vascular injury, remain unknown.

The neointimal formation model in rats was established by carotid artery balloon injury using a 2F-Forgaty catheter. Most Sca-1+ cells first appeared at the adventitia of the vascular wall. S100B expressions were highest within the adventitia on the first day after vessel injury. Along with the sequentially increasing trend of S100B expression in the intima, media, and adventitia, respectively, the numbers of Sca-1+ cells were prominently increased at the media or neointima during the time course of neointimal formation. Furthermore, the Sca-1+ cells were markedly increased in the tunica media on the third day of vessel injury, SDF-1α expressions were obviously increased, and SDF-1α levels and Sca-1+ cells were almost synchronously increased within the neointima on the seventh day of vessel injury. These effects could effectually be reversed by knockdown of S100B by shRNA, RAGE inhibitor (SPF-ZM1), or CXCR4 blocker (AMD3100), indicating that migration of Sca-1+ cells from the adventitia into the neointima was associated with S100B/RAGE and SDF-1α/CXCR4. More importantly, the intermediate state of double-positive Sca-1+ and α-SMA cells was first found in the neointima of injured arteries, which could be substantially abrogated by using shRNA for S100B or blockade of CXCR4. S100B dose-dependently regulated SDF-1α expressions in VSMCs by activating PI3K/AKT and NF-κB, which were markedly abolished by PI3K/AKT inhibitor wortmannin and enhanced by p65 blocker PDTC. Furthermore, S100B was involved in human umbilical cord-derived Sca-1+ progenitor cells’ differentiation into VSMCs, especially in maintaining the intermediate state of double-positive Sca-1+ and α-SMA.

S100B triggered neointimal formation in rat injured arteries by maintaining the intermediate state of double-positive Sca-1+ progenitor and VSMCs, which were associated with direct activation of RAGE by S100B and indirect induction of SDF-1α by activating PI3K/AKT and NF-κB.

The online version of this article (10.1186/s13287-019-1400-0) contains supplementary material, which is available to authorized users.

• Intermediate state
• NF-κB
• Neointima
• S100B
• SDF-1α
• Sca-1

Vascular calcification (VC), characterized by hydroxyapatite crystal depositing in the vessel wall, is a common pathological condition shared by many chronic diseases and an independent risk factor for cardiovascular events. Recently, VC is regarded as an active, dynamic cell-mediated process, during which calcifying cell transition is critical. Mesenchymal stem cells (MSCs), with a multidirectional differentiation ability and great potential for clinical application, play a duplex role in the VC process. MSCs facilitate VC mainly through osteogenic transformation and apoptosis. Meanwhile, several studies have reported the protective role of MSCs. Anti-inflammation, blockade of the BMP2 signal, downregulation of the Wnt signal, and antiapoptosis through paracrine signaling are possible mechanisms. This review displays the evidence both on the facilitating role and on the protective role of MSCs, then discusses the key factors determining this divergence.

• atherosclerosis
• migration
• progenitor cells
• stem cells

• Bone marrow
• Differentiation
• Hematopoietic stem cells
• Mesenchymal stem cells
• Osteoblast

• atherosclerosis
• pericytes
• progenitor cells
• stem cells
• vascular calcification

• Arterial stiffness
• Cardiovascular disease
• Hypertension
• Vascular calcification

• Chronic kidney disease
• High phosphate
• Osteogenic differentiation
• PPARγ
• Vascular calcification

• Autophagy
• Osteoblast-like cells
• Signaling pathways
• Vascular calcification

• Calcifying cells
• Review
• Signaling pathway
• Vascular calcification

Vascular calcification (VC) is often associated with cardiovascular and metabolic diseases. However, the molecular mechanisms linking VC to these diseases have yet to be elucidated. Here we report that MDM2-induced ubiquitination of histone deacetylase 1 (HDAC1) mediates VC. Loss of HDAC1 activity via either chemical inhibitor or genetic ablation enhances VC. HDAC1 protein, but not mRNA, is reduced in cell and animal calcification models and in human calcified coronary artery. Under calcification-inducing conditions, proteasomal degradation of HDAC1 precedes VC and it is mediated by MDM2 E3 ubiquitin ligase that initiates HDAC1 K74 ubiquitination. Overexpression of MDM2 enhances VC, whereas loss of MDM2 blunts it. Decoy peptide spanning HDAC1 K74 and RG 7112, an MDM2 inhibitor, prevent VC in vivo and in vitro. These results uncover a previously unappreciated ubiquitination pathway and suggest MDM2-mediated HDAC1 ubiquitination as a new therapeutic target in VC.

Vascular calcification (VC) increases morbidity and mortality in cardiovascular and metabolic diseases. Here, Kwon et al. show that calcification stimuli induce MDM2- mediated ubiquitination and proteasomal degradation of HDAC1, suggesting a possible therapeutic strategy for treatment of VC patients.

• atherosclerosis
• endothelial progenitor cells
• macrophage progenitor cells
• mesenchymal stem cells
• smooth muscle progenitor cells

Vascular smooth muscle cells (SMCs), a major structural component of the vessel wall, not only play a key role in maintaining vascular structure but also perform various functions. During embryogenesis, SMC recruitment from their progenitors is an important step in the formation of the embryonic vascular system. SMCs in the arterial wall are mostly quiescent but can display a contractile phenotype in adults. Under pathophysiological conditions, i.e. vascular remodelling after endothelial dysfunction or damage, contractile SMCs found in the media switch to a secretory type, which will facilitate their ability to migrate to the intima and proliferate to contribute to neointimal lesions. However, recent evidence suggests that the mobilization and recruitment of abundant stem/progenitor cells present in the vessel wall are largely responsible for SMC accumulation in the intima during vascular remodelling such as neointimal hyperplasia and arteriosclerosis. Therefore, understanding the regulatory mechanisms that control SMC differentiation from vascular progenitors is essential for exploring therapeutic targets for potential clinical applications. In this article, we review the origin and differentiation of SMCs from stem/progenitor cells during cardiovascular development and in the adult, highlighting the environmental cues and signalling pathways that control phenotypic modulation within the vasculature.

• Calcification
• Mesenchymal stem cells
• MicroRNA-30e
• Osteogenesis
• Smooth muscle cells

The term ‘‘Stammzelle’’ (stem cells) originally appeared in 1868 in the works of Ernst Haeckel who used it to describe the ancestor unicellular organism from which he presumed all multicellular organisms evolved. Since then stem cells have been studied in a wide spectrum of normal and pathological conditions; it is remarkable to note that ectopic arterial calcification was considered a passive deposit of calcium since its original discovering in 1877; in the last decades, resident and circulating stem cells were imaged to drive arterial calcification through chondro-osteogenic differentiation thus opening the idea that an active mechanism could be at the basis of the process that clinically shows a Janus effect: calcifications either lead to the stabilization or rupture of the atherosclerotic plaques. A review of the literature underlines that 130 years after stem cell discovery, antigenic markers of stem cells are still debated and the identification of the osteoprogenitor phenotype is even more elusive due to tissue degradation occurring at processing and manipulation. It is necessary to find a consensus to perform comparable studies that implies phenotypic recognition of stem cells antigens. A hypothesis is based on the singular morphology and amitotic mechanism of division of osteoclasts: it constitutes the opening to a new approach on osteoprogenitors markers and recognition. Our aim was to highlight all the present evidences of the active calcification process, summarize the different cellular types involved, and discuss a novel approach to discover osteoprogenitor phenotypes in arterial wall.

• Osteocalcin
• Osteoprogenitor
• Stem cells markers
• Arterial calcification
• Resident and circulating

• bone morphogenetic protein
• endothelium
• matrix Gla protein
• progenitor cells
• vascular calcification

• Animals
• Aorta/cytology
• Calcinosis/physiopathology
• Calcium-Binding Proteins/deficiency
• Calcium-Binding Proteins/genetics
• Calcium-Binding Proteins/physiology
• Cell Lineage
• Cell Transdifferentiation/physiology
• Cells, Cultured/drug effects
• Diabetes Mellitus, Type 2/genetics
• Diabetic Angiopathies/genetics
• Diabetic Angiopathies/physiopathology
• Disease Models, Animal
• Endothelial Cells/pathology
• Endothelium, Vascular/pathology
• Endothelium, Vascular/physiopathology
• Extracellular Matrix Proteins/deficiency
• Extracellular Matrix Proteins/genetics
• Extracellular Matrix Proteins/physiology
• Glucose/pharmacology
• Heterozygote
• Humans
• Insulin/genetics
• Insulin/physiology
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Mice, Transgenic
• Microfilament Proteins/physiology
• Multipotent Stem Cells/pathology
• Muscle Proteins/physiology
• RNA, Small Interfering/pharmacology
• Receptor, TIE-2/genetics
• Recombinant Fusion Proteins/physiology
• Signal Transduction
• Vascular Diseases/physiopathology
• Matrix Gla Protein

• R01 HL112839 NHLBI NIH HHS
• HL112839 NHLBI NIH HHS
• HL30568 NHLBI NIH HHS
• NS79353 NINDS NIH HHS
• HL81397 NHLBI NIH HHS
• R01 NS079353 NINDS NIH HHS
• DP3 DK094311 NIDDK NIH HHS
• R01 HL081397 NHLBI NIH HHS
• P01 HL030568 NHLBI NIH HHS