Endothelial Progenitor Cells Dysfunction Research Articles

The Expression of Circ-Astn1 Inhibits High Glucose Induced Endothelial Progenitor Cell Dysfunction by Activating Autophagy

ABSTRACT Background Diabetes mellitus (DM) and complications such as chronic kidney disease and cardiovascular symptoms pose a substantial public health burden. Increasing studies have shown that circular RNAs (circRNAs) regulate many gene expressions that are essential in diverse pathological and biological procedures. However, the roles of particular circRNAs in DM are unclear. Methods In the current investigation, endothelial progenitor cells (EPCs) were used to search for abnormal expression of circRNAs by using high-throughput sequencing under high glucose (HG) conditions. The regulatory mechanisms and targets were then studied through bioinformatics analysis, luciferase reporter analysis, angiogenic differentiation experiments, flow cytometry detection of apoptosis and RT-qPCR analysis. Results The circ-Astn1 expression in EPCs decreased after HG treatment. Overexpression or circ-Astn1 suppressed HG induced endothelial cell damage. MicroRNA (miR)-138-5p and SIRT5 were found to be the downstream targets of circ-Astn1 through luciferase reporter analysis. SIRT5 downregulation or miR-138-5p overexpression reversed circ-Astn1’s protective effect against HG induced endothelial cell dysfunction, including apoptosis and abnormal vascular differentiation. Furthermore, circ-Astn1 overexpression promoted autophagy activation by increasing SIRT5 expression under HG conditions. Our findings suggest that circ-Astn1 mediated promotion of SIRT5 facilitates autophagy by sponging miR-138-5p. Conlusion Together, our findings show that the overexpression of circ-Astn1 suppresses HG induced endothelial cell damage by targeting miR-138-5p/SIRT5 axis.

Potential role of endothelial progenitor cells in the pathogenesis and treatment of cerebral aneurysm.

Cerebral aneurysm (CA) is a significant health concern that results from pathological dilations of blood vessels in the brain and can lead to severe and potentially life-threatening conditions. While the pathogenesis of CA is complex, emerging studies suggest that endothelial progenitor cells (EPCs) play a crucial role. In this paper, we conducted a comprehensive literature review to investigate the potential role of EPCs in the pathogenesis and treatment of CA. Current research indicates that a decreased count and dysfunction of EPCs disrupt the balance between endothelial dysfunction and repair, thus increasing the risk of CA formation. Reversing these EPCs abnormalities may reduce the progression of vascular degeneration after aneurysm induction, indicating EPCs as a promising target for developing new therapeutic strategies to facilitate CA repair. This has motivated researchers to develop novel treatment options, including drug applications, endovascular-combined and tissue engineering therapies. Although preclinical studies have shown promising results, there is still a considerable way to go before clinical translation and eventual benefits for patients. Nonetheless, these findings offer hope for improving the treatment and management of this condition.

Formulation and Characterization of Nanoparticle-Protein Sirtuin 1 (NPS1) by Nanoprecipitation Technique

Atherosclerosis is a cardiovascular disease caused by endothelial dysfunction. This situation will trigger the bone marrow to immediately replace it with new endothelial progenitor cells (EPC) cells. However, some studies suggest that EPC can experience premature senescence. Sirtuin-1 (SIRT1) is a cellular post-translational protein that has the task of repairing dysfunctional EPC cells. Studies have tried to develop SIRT1 activation, but currently, there are no studies that have attempted to increase SIRT1 levels in cells. Nanoparticles (NPS) are one of the methods in nanomedicine, which has the advantage of being a drug carrier. So, further research is needed on adding exogenous SIRT1 levels, NPS, which can improve the quality of EPC cells and prevent premature senescence. This study aims to report the formulation and characterization stages of nanoparticles carrying SIRT1 (NPS1) with different solvents, such as ethanol and aquadest. The method used in this formulation uses nanoprecipitation. The characterization of nanoparticles at this stage included organoleptic tests, pH tests, and quantifying using Nanodrops in determining the presence of adsorbed proteins. The pH and organoleptic test showed that the NPS1 formulation was acidic (K1 = 5.412 ± 0.73; K2 = 3.624 ± 0.45; F1 = 5.418 ± 0.55; F2 = 4.182 ± 0.07), yellow in color, and had a characteristic odor. Thus, the formulation and characteristics of NPS1 can be used as a method in drug development for anti-senescence therapy in EPC cells in further research, both in vitro, in vivo, and evaluation of preparations that are still very possible to be developed.

Lycopene inhibits pyroptosis of endothelial progenitor cells induced by ox-LDL through the AMPK/mTOR/NLRP3 pathway.

The malfunction of endothelial progenitor cells (EPCs) due to ox-LDL is a risk contributor for arteriosclerotic disease. Meanwhile, lycopene possesses anti-inflammatory and antioxidative qualities. This investigation aimed to determine if lycopene can protect EPCs from ox-LDL-induced damage and to elucidate the underlying mechanism. The effects of lycopene on the survival, migration, and tube-forming capacity of EPCs were determined via in vitro assays. Expression of proteins related to pyroptosis and cellular proteins related to AMPK/mTOR/NLRP3 signaling was determined by western blot/flow cytometry. Our results demonstrated that lycopene treatment significantly enhanced proliferation, tube formation, and migration of EPCs stimulated by ox-LDL. Additionally, lycopene was found to suppress pyroptosis in ox-LDL-induced EPCs through the activation of AMPK, which led to the inhibition of mTOR phosphorylation and subsequent downregulation of the downstream NLRP3 inflammasome. In summary, our study suggests that lycopene mitigates ox-LDL-induced dysfunction in EPCs and inhibits pyroptosis via AMPK/mTOR/NLRP3 signaling. Our study suggests that lycopene may act as promising therapies for preventing atherosclerosis.

AMPK deficiency inhibits fatty acid oxidation in endothelial progenitor cells to aggravate impaired angiogenesis after ischemic stroke in hyperlipidemic mice

ABSTRACT Background Hyperlipidemia is a risk factor for stroke, and worsens neurological outcome after stroke. Endothelial progenitor cells (EPCs), which become dysfunctional in cerebral ischemia, hold capacity to promote revascularization. Objective We investigated the role of dyslipidemia in impairment of EPC-mediated angiogenesis in cerebral ischemic mice. Methods and Results The high fat diet (HFD)-fed mice following by ischemic stroke exhibited increased infarct volumes and neurological severity scores, and poorer angiogenesis. Bone marrow-EPCs treated with palmitic acid (PA) showed impaired functions and inhibited activity of AMP-activated protein kinase (AMPK). Notably, AMPK deficiency aggravated EPC dysfunction, further decreased mitochondrial membrane potential, and increased reactive oxygen species level in EPCs with PA treatment. Furthermore, the expression of fatty acid oxidation (FAO)-related genes was remarkably reduced, and carnitine palmitoyltransferase 1A (CPT1A) protein expression was downregulated in AMPK-deficient EPCs. AMPK deficiency aggravated neurological severity scores and angiogenesis in ischemic brain of HFD-fed mice, accompanied by suppressed protein level of CPT1A. EPC transplantation corrected impaired neurological severity scores and angiogenesis in AMPK-deficient mice. Conclusion Our findings suggest that AMPK deficiency aggravates poor angiogenesis in ischemic brain by mediating FAO and oxidative stress thereby inducing EPC dysfunction in hyperlipidemic mice.

Activation of PPARδ in bone marrow endothelial progenitor cells improves their hematopoiesis-supporting ability after myelosuppressive injury

Dysfunctional bone marrow (BM) endothelial progenitor cells (EPCs) with high levels of reactive oxygen species (ROS) are responsible for defective hematopoiesis in poor graft function (PGF) patients with acute leukemia or myelodysplastic neoplasms post-allotransplant. However, the underlying mechanism by which BM EPCs regulate their intracellular ROS levels and the capacity to support hematopoiesis have not been well clarified. Herein, we demonstrated decreased levels of peroxisome proliferator-activated receptor delta (PPARδ), a lipid-activated nuclear receptor, in BM EPCs of PGF patients compared with those with good graft function (GGF). In vitro assays further identified that PPARδ knockdown contributed to reduced and dysfunctional BM EPCs, characterized by the impaired ability to support hematopoiesis, which were restored by PPARδ overexpression. Moreover, GW501516, an agonist of PPARδ, repaired the damaged BM EPCs triggered by 5-fluorouracil (5FU) in vitro and in vivo. Clinically, activation of PPARδ by GW501516 benefited the damaged BM EPCs from PGF patients or acute leukemia patients in complete remission (CR) post-chemotherapy. Mechanistically, we found that increased expression of NADPH oxidases (NOXs), the main ROS-generating enzymes, may lead to elevated ROS level in BM EPCs, and insufficient PPARδ may trigger BM EPC damage via ROS/p53 pathway. Collectively, we found that defective PPARδ contributes to BM EPC dysfunction, whereas activation of PPARδ in BM EPCs improves their hematopoiesis-supporting ability after myelosuppressive therapy, which may provide a potential therapeutic target not only for patients with leukemia but also for those with other cancers.

PU.1 alleviates the inhibitory effects of cigarette smoke on endothelial progenitor cell function and lung-homing through Wnt/β-catenin and CXCL12/CXCR4 pathways.

Endothelial progenitor cells (EPCs) dysfunction is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). The transcription factor PU.1 is essential for the maintenance of stem/progenitor cell homeostasis. However, the role of PU.1 in COPD and its effects on EPC function and lung-homing, remain unclear. This study aimed to explore the protective activity of PU.1 and the underlying mechanisms in a cigarette smoke extract (CSE)-induced emphysema mouse model. C57BL/6 mice were treated with CSE to establish a murine emphysema model and injected with overexpressed PU.1 or negative control adeno-associated virus. Morphometry of lung slides, lung function, and apoptosis of lung tissues were evaluated. Immunofluorescence co-localization was used to analyze EPCs homing into the lung. Flow cytometry was performed to detect EPC count in lung tissues and bone marrow (BM). The angiogenic ability of BM-derived EPCs cultured in vitro was examined by tube formation assay. We determined the expression levels of PU.1, β-catenin, C-X-C motif ligand 12 (CXCL12), C-X-C motif receptor 4 (CXCR4), stem cell antigen-1 (Sca-1), and stemness genes. CSE exposure significantly reduced the expression of PU.1 in mouse lung tissues, BM, and BM-derived EPCs. PU.1 overexpression attenuated CSE-induced emphysematous changes, lung function decline, and apoptosis. In emphysematous mice, PU.1 overexpression markedly reversed the decreased proportion of EPCs in BM and promoted the lung-homing of EPCs. The impaired angiogenic ability of BM-derived EPCs induced by CSE could be restored by the overexpression of PU.1. In addition, PU.1 upregulation evidently reversed the decreased expression of β-catenin, CXCL12, CXCR4, Scal-1, and stemness genes in mouse lung tissues, BM, and BM-derived EPCs after CSE exposure. PU.1 alleviates the inhibitory effects of CSE on EPC function and lung-homing via activating the canonical Wnt/β-catenin pathway and CXCL12/CXCR4 axis. While further research is needed, our research may indicate a potential therapeutic target for COPD patients.

Mitochondrial Dysfunction in Endothelial Progenitor Cells: Unraveling Insights from Vascular Endothelial Cells.

Endothelial dysfunction is associated with several lifestyle-related diseases, including cardiovascular and neurodegenerative diseases, and it contributes significantly to the global health burden. Recent research indicates a link between cardiovascular risk factors (CVRFs), excessive production of reactive oxygen species (ROS), mitochondrial impairment, and endothelial dysfunction. Circulating endothelial progenitor cells (EPCs) are recruited into the vessel wall to maintain appropriate endothelial function, repair, and angiogenesis. After attachment, EPCs differentiate into mature endothelial cells (ECs). Like ECs, EPCs are also susceptible to CVRFs, including metabolic dysfunction and chronic inflammation. Therefore, mitochondrial dysfunction of EPCs may have long-term effects on the function of the mature ECs into which EPCs differentiate, particularly in the presence of endothelial damage. However, a link between CVRFs and impaired mitochondrial function in EPCs has hardly been investigated. In this review, we aim to consolidate existing knowledge on the development of mitochondrial and endothelial dysfunction in the vascular endothelium, place it in the context of recent studies investigating the consequences of CVRFs on EPCs, and discuss the role of mitochondrial dysfunction. Thus, we aim to gain a comprehensive understanding of mechanisms involved in EPC deterioration in relation to CVRFs and address potential therapeutic interventions targeting mitochondrial health to promote endothelial function.

Diabetic Vasculopathy: Molecular Mechanisms and Clinical Insights.

Clinical and basic studies have documented that both hyperglycemia and insulin-resistance/hyperinsulinemia not only constitute metabolic disorders contributing to cardiometabolic syndrome, but also predispose to diabetic vasculopathy, which refers to diabetes-mellitus-induced microvascular and macrovascular complications, including retinopathy, neuropathy, atherosclerosis, coronary artery disease, hypertension, and peripheral artery disease. The underlying molecular and cellular mechanisms include inappropriate activation of the renin angiotensin-aldosterone system, mitochondrial dysfunction, excessive oxidative stress, inflammation, dyslipidemia, and thrombosis. These abnormalities collectively promote metabolic disorders and further promote diabetic vasculopathy. Recent evidence has revealed that endothelial progenitor cell dysfunction, gut dysbiosis, and the abnormal release of extracellular vesicles and their carried microRNAs also contribute to the development and progression of diabetic vasculopathy. Therefore, clinical control and treatment of diabetes mellitus, as well as the development of novel therapeutic strategies are crucial in preventing cardiometabolic syndrome and related diabetic vasculopathy. The present review focuses on the relationship between insulin resistance and diabetes mellitus in diabetic vasculopathy and related cardiovascular disease, highlighting epidemiology and clinical characteristics, pathophysiology, and molecular mechanisms, as well as management strategies.

14-3-3-η interacts with BCL-2 to protect human endothelial progenitor cells from ox-LDL-triggered damage.

Oxidized low-density lipoprotein (ox-LDL) causes dysfunction of endothelial progenitor cells (EPCs), and we recently reported that 14-3-3-η can attenuate the damage triggered by ox-LDL in EPCs. However, the molecular mechanisms by which 14-3-3-η protects EPCs from the damage caused by ox-LDL are not fully understood. In this study, we observed that the expression of 14-3-3-η and BCL-2 were downregulated in ox-LDL-treated EPCs. Overexpression of 14-3-3-η in ox-LDL-treated EPC significantly increased BCL-2 level, while knockdown of BCL-2 reduced 14-3-3-η expression and mitigated the protective effect of 14-3-3-η on EPCs. In addition, we discovered that 14-3-3-η colocalizes and interacts with BCL-2 in EPCs. Taken together, these data suggest that 14-3-3-η protects EPCs from ox-LDL-induced damage by its interaction with BCL-2.

Tumor necrosis factor superfamily 14 (TNFSF14/ LIGHT) attenuates neovascularization by reducing circulating endothelial progenitor cells and function

Abstract Background Tumor necrosis factor superfamily 14 (TNFSF14) is also known as LT-related inducible ligand that competes for glycoprotein D binding to herpesvirus entry mediator on T cells (LIGHT) can bind to herpesvirus invasion mediator and lymphotoxin-β receptor to perform its biological activity. LIGHT signaling strengthens the synthesis of nitric oxide, reactive oxygen species, and cytokines and affects organ function. LIGHT also stimulates angiogenesis in tumors and induces synthesis of high endothelial venules, degrades extracellular matrix in thoracic aortic dissection, induces the expression of interleukin-8, cyclooxygenase-2, and cell adhesion molecules in endothelial cells. While LIGHT induces tissue inflammation, its effects on angiogenesis after tissue ischemia are unclear. Thus, we analyzed this effect in the current study. Methods C57BL/6 mice underwent hind limb ischemia surgery for model construction. Doppler ultrasound, immunohistochemical staining, and western blotting were employed to analyze the effects of LIGHT on angiogenesis. In addition, human endothelial progenitor cells (EPCs) were used for in vitro studies to analyze the possible mechanisms. Results In the mice, LIGHT injection inhibited angiogenesis in ischemic limbs. In vitro, LIGHT inhibited the expression of integrins and E-selectin; decreased migration and tube formation capabilities, mitochondrial respiration, and succinate dehydrogenase activity; and promoted senescence in EPCs. Western blotting revealed that the impairment of EPC function by LIGHT may be due to its effects on the normal operation of intracellular Akt signaling pathway and endothelial nitrite oxide synthase (eNOS) function. Conclusions LIGHT inhibits angiogenesis after tissue ischemia. LIGHT inhibition of intracellular Akt-eNOS signaling axis and mitochondrial respiration in EPCs impair cell function. These events are the possible causes of impaired angiogenesis.LIGHT decreases the recovery of ischemiaSenescence and dysfunction of EPC

Impaired Angiogenic Function of Fetal Endothelial Progenitor Cells via PCDH10 in Gestational Diabetes Mellitus.

Maternal hyperglycemia, induced by gestational diabetes mellitus (GDM), has detrimental effects on fetal vascular development, ultimately increasing the risk of cardiovascular diseases in offspring. The potential underlying mechanisms through which these complications occur are due to functional impairment and epigenetic changes in fetal endothelial progenitor cells (EPCs), which remain less defined. We confirm that intrauterine hyperglycemia leads to the impaired angiogenic function of fetal EPCs, as observed through functional assays of outgrowth endothelial cells (OECs) derived from fetal EPCs of GDM pregnancies (GDM-EPCs). Notably, PCDH10 expression is increased in OECs derived from GDM-EPCs, which is associated with the inhibition of angiogenic function in fetal EPCs. Additionally, increased PCDH10 expression is correlated with the hypomethylation of the PCDH10 promoter. Our findings demonstrate that in utero exposure to GDM can induce angiogenic dysfunction in fetal EPCs through altered gene expression and epigenetic changes, consequently increasing the susceptibility to cardiovascular diseases in the offspring of GDM mothers.

Transplantation of endothelial progenitor cells improves myocardial hypertrophy in spontaneously hypertensive rats through HO-1/CREB3/AKT axis

Hypertensive myocardial hypertrophy produces a hostile microenvironment characterized by cardiomyocyte hypertrophy, inflammation and oxidative stress, which also leads to endothelial progenitor cells (EPCs) dysfunction, preventing EPC migration, adhesion and angiogenesis. Heme oxygenase-1 (HO-1) is an intracellular protein that plays an important role in angiogenesis and cell survival. The upregulation of cAMP response element-binding protein 3 (CREB3) is closely related to the formation of endothelial cells. The purpose of this study was to evaluate the role of HO-1 and CREB3 in EPCs and their effects on hypertensive myocardial hypertrophy. EPCs were transfected with HO-1 adenoviral overexpression vector (Ad–HO–1) or together with CREB3 siRNA (si-CREB3), or transfected with CREB3 adenoviral overexpression vector (Ad-CREB3) or together with HO-1 siRNA, and then treated with 100 nM Ang Ⅱ for 12 h. Overexpressing HO-1 or CREB3 promoted adhesion to extracellular matrix, cell migration, and angiogenesis, inhibited the secretion of inflammatory factors TNF-α and IL-6, and reduced ROS level, ICAM-1 and MCP-1 mRNA expression levels in EPCs treated with Ang Ⅱ. Online prediction and Co-IP assay showed that HO-1 interacts with CREB3, and they promote expression of each other. EPC-conditioned medium supplemented with CREB3 recombinant protein decreased the levels of ANP and BNP mRNA in H9C2 cells treated with Ang Ⅱ and alleviated oxidative stress. Ad-CREB3 transfected EPCs promoted the phosphorylation of AKT in vivo and in vitro, thereby improving myocardial swelling and dysfunction in SHR rats. Taken together, transplantation of CREB3 overexpressing EPCs alleviates myocardial hypertrophy in spontaneously hypertensive rats by promoting HO-1 protein expression and AKT phosphorylation.

Loxenatide attenuates ROS-mediated vascular endothelial progenitor cell damage and mitochondrial dysfunction via SIRT3/Foxo3 signaling pathway.

Diabetes mellitus (DM), becomes a main public health issue worldwide due to the rapid increase in DM patient numbers. The dysfunction of endothelial progenitor cells (EPCs) in DM patients plays a critical role in endothelial repair and the progression of DM-related vascular complications. Loxenatide is an a glucagon-like peptide 1 receptor agonist, which is used to control glycemic in type 2 diabetes patients. However, the role of Loxenatide in EPCs remains to be investigated. EPCs were isolated, characterized, and treated with Loxenatide, high-glucose, or 3-TYP. quantitative real-time polymerase chain reaction, flow cytometry, western blot, and cell counting kit-8 assay were employed to validate the expression of gene and protein expressions and cell viability, respectively. Application of Seahorse XFp to measure oxygen consumption and mitochondrial membrane potential (MMP) were measured by Seahorse XFp and MMP assay. Loxenatide attenuated high-glucose-induced reactive oxygen species (ROS) production and mitochondrial-dependent apoptosis of EPCs in a concentration-dependent manner. The EPC mitochondrial respiration dysfunction induced by high glucose was also repressed by the loxenatide treatment. The protection effect of Loxenatide on EPCs against high-glucose was applied by activating the sirtuin 3 (SIRT3)/Foxo3 signaling pathway. We demonstrated the regulatory role of Loxenatide in mitochondrial dysfunction and apoptosis of EPCs. We elucidated that Loxenatide protects EPC from high-glucose-induced apoptosis via ROS-mediated mitochondrial pathway through the SIRT3/Foxo3 signing pathway. This may provide a new therapeutical target for the treatment of DM-related vascular complications.

LINC00659 exacerbates endothelial progenitor cell dysfunction in deep vein thrombosis of the lower extremities by activating DNMT3A-mediated FGF1 promoter methylation

It has been shown that long non-coding RNA (lncRNA) LINC00659 was markedly upregulated in the peripheral blood of patients with deep venous thrombosis (DVT). However, the function of LINC00659 in lower extremity DVT (LEDVT) remains to be largely unrevealed. A total of 30 inferior vena cava (IVC) tissue samples and peripheral blood (60 ml per subject) were obtained from LEDVT patients (n = 15) and healthy donors (n = 15), and then LINC00659 expression was detected by RT-qPCR. The results displayed that LINC00659 is upregulated in IVC tissues and isolated endothelial group cells (EPCs) of patients with LEDVT. LINC00659 knock-down promoted the proliferation, migration, and angiogenesis ability of EPCs, while an pcDNA-eukaryotic translation initiation factor 4A3 (EIF4A3), a EIF4A3 overexpression vector, or fibroblast growth factor 1 (FGF1) small interfering RNA (siRNA) combined with LINC00659 siRNA could not enhance this effect. Mechanistically, LINC00659 bound with EIF4A3 promoter to upregulated EIF4A3 expression. Besides, EIF4A3 could facilitate FGF1 methylation and its downregulated expression by recruiting DNA methyltransferases 3A (DNMT3A) to the FGF1 promoter region. Additionally, LINC00659 inhibition could alleviate LEDVT in mice. In summary, the data indicated the roles of LINC00659 in the pathogenesis of LEDVT, and the LINC00659/EIF4A3/FGF1 axis could be a novel therapeutic target for the treatment of LEDVT.

Transplantation of endothelial progenitor cells overexpressing mir-126-3p improves vascular repair in a diabetic rat model.

Transplantation of endothelial progenitor cells overexpressing mir-126-3p improves vascular repair in a diabetic rat model.

S-38-3: LONG NONCODING RNA P21 ALLEVIATES ENDOTHELIAL PROGENITOR CELLS DAMAGE AND PROMOTES ENDOTHELIAL REPAIR IN HYPERTENSION THROUGH ENHANCING AUTOPHAGY

Objective: Vascular damage of hypertension has been the focus of hypertension treatment, and endothelial progenitor cells (EPCs) play an important role in the repair of vascular endothelial damage. Functional damage and decreased number of EPCs are observed in the peripheral circulation of hypertensive patients, but its mechanism is not yet elucidated. Methods: Peripheral circulating endothelial progenitor cells of hypertensive patients were labeled and detected by flow cytometry. At the same time, the endothelial progenitor cells of hypertensive patients were cultured in vitro to detect their cell function and aging. The rat bone marrow-derived endothelial progenitor cells were isolated and cultured in vitro. After the intervention of AngII, the cell function, autophagy, and cell senescence were detected. PCR and WB were used to measure the expression and phosphorylation of SESN2, AMPK and TSC2. Results: Our results showed that the number of EPCs in hypertensive patients is significantly lower than that of normal population, and the cell function decreases with a higher proportion of EPCs at later stages. A decrease in autophagy is responsible for the senescence and damage of EPCs induced by AngII. Moreover, lncRNA-p21 plays a critical regulator role in the senescence and dysfunction of EPCs. Furthermore, lncRNA-p21 activates SESN2/AMPK/TSC2 pathway by promoting the transcriptional activity of p53 and lncRNA-p21 overexpression enhanced autophagy via AMPK/TSC2/mTOR pathway to protect against AngII-induced EPC damage. EPCs with lncRNA-p21 knockdown showed poor adhesion ability and vascular repair function. These results suggest that lncRNA-p21 enhances autophagy to alleviate endothelial progenitor cells damage and promote endothelial repair in hypertension through SESN2/AMPK/TSC2 pathway. Conclusion: The data provide evidence that a reversal of decreased autophagy serves as the protective mechanism of EPC injury in hypertensive patients, and lncRNA-p21 is a new therapeutic target for vascular endothelial repair in hypertension.

The vascular phenotype of BPD: new basic science insights-new precision medicine approaches.

Bronchopulmonary dysplasia (BPD) is the most common complication of preterm birth. Up to 1/3 of children with BPD develop pulmonary hypertension (PH). PH increases mortality, the risk of adverse neurodevelopmental outcome and lacks effective treatment. Current vasodilator therapies address symptoms, but not the underlying arrested vascular development. Recent insights into placental biology and novel technological advances enabling the study of normal and impaired lung development at the single cell level support the concept of a vascular phenotype of BPD. Dysregulation of growth factor pathways results in depletion and dysfunction of putative distal pulmonary endothelial progenitor cells including Cap1, Cap2, and endothelial colony-forming cells (ECFCs), a subset of vascular progenitor cells with self-renewal and de novo angiogenic capacity. Preclinical data demonstrate effectiveness of ECFCs and ECFC-derived particles including extracellular vesicles (EVs) in promoting lung vascular growth and reversing PH, but the mechanism is unknown. The lack of engraftment suggests a paracrine mode of action mediated by EVs that contain miRNA. Aberrant miRNA signaling contributes to arrested pulmonary vascular development, hence using EV- and miRNA-based therapies is a promising strategy to prevent the development of BPD-PH. More needs to be learned about disrupted pathways, timing of intervention, and mode of delivery. IMPACT: Single-cell RNA sequencing studies provide new in-depth view of developmental endothelial depletion underlying BPD-PH. Aberrant miRNA expression is a major cause of arrested pulmonary development. EV- and miRNA-based therapies are very promising therapeutic strategies to improve prognosis in BPD-PH.

Circulating endothelial progenitor cell dysfunction in patients with bipolar disorder.

Dysfunction in circulating endothelial progenitor cells (cEPCs) plays a crucial role in cardiovascular disorders (CVDs). Patients with bipolar disorder (BPD) are at increased risk of developing CVDs. This study examined the associations of the functional properties of cEPCs with BPD and its clinical and cognitive characteristics. We recruited 69 patients with BPD and 41 healthy controls (HCs). The levels of manic, depressive, anxiety, psychosomatic symptoms, subjective cognitive dysfunction, quality of life, and functional disability of the BPD group were evaluated using the Young Mania Rating Scale (YMRS), Clinical Global Impression for BPD (CGI-BP), Hamilton Depression Rating Scale, Montgomery-Åsberg Depression Rating Scale, Hamilton Anxiety Rating Scale, Depression and Somatic Symptoms Scale, Perceived Deficits Questionnaire-Depression, 12-Item Short-Form Health Survey, and Sheehan Disability Scale, respectively. Cognitive function was assessed using 2-back and Go/No-Go tasks. Through in vitro assays, the adhesion to fibronectin and the percentage of apoptosis of cEPCs were examined. Under correction for multiple comparisons, the adhesive function of cEPCs in BPD was significantly lower than that in the HCs (corrected P [Pcorr] = 0.027). The reduced adhesive function of cEPCs correlated significantly with increased scores in the YMRS (Pcorr = 0.0002) and the CGI-BP (Pcorr = 0.0009). A lower percentage of apoptotic cEPC cells was associated with greater commission errors in the 2-back (Pcorr = 0.028) and Go/No-Go tasks (Pcorr = 0.029). The cEPCs of the BPD group exhibited attenuated adhesive function. The altered adhesive and apoptotic functions of cEPCs are associated with manic symptom severity and response inhibition deficits in patients with BPD.

Andrographolide improves the dysfunction of endothelial progenitor cells from angiotensin II-induced hypertensive mice through SIRT1 signaling

Endothelial progenitor cells (EPCs) are crucial for the maintenance of vascular homeostasis. The dysfunction of EPCs contributes to the endothelial damage in hypertension. Andrographolide (AGP) is a traditional Chinese patent medicine that has been reported to have protective effects on cardiovascular system. However, the effect of AGP on the function of EPCs in hypertension remains unknown. In this study, we aimed to elucidate the effect of AGP on EPCs and the underlying mechanisms. In vivo, the blood pressure and endothelial function (indicated by endothelial dependent vasodilation) of AGP-fed angiotensin II (Ang II)-infused hypertensive mice were examined. In vitro, the function of EPCs isolated from bone marrow were evaluated by tube formation, migration, and adhesion assay. Additionally, a silent information regulator 1 (SIRT1) inhibitor/agonist and a small interfering RNA (si-RNA) targeting SIRT1 were used to determine the pathway involved. The results showed that AGP not only reduced blood pressure, improved endothelial function in hypertensive mice but also restored the dysfunction of EPCs of hypertension in vitro. Mechanistically, AGP up-regulated SIRT1 expression, decreased the Bax/Bcl-2 ratio and the expression level of Cleaved caspase-3, thus inhibiting the apoptosis of Ang II induced EPCs. However, the beneficial effects of AGP on EPCs disappeared after the inhibition or the knockdown of SIRT1. To summarize, this study demonstrates for the first time that AGP improves the dysfunction of EPCs through SIRT1-mediated anti-apoptotic effects. Our findings might provide a novel therapeutic strategy for treating vascular damage in hypertension.