Function Of Endothelial Progenitor Cells Research Articles

The Role of Nanopartikel Green Tea in Enhancing Endothelial Cell Migration in HUVEC Culture exposed to EPC-Conditioned Media in Hyperglycemic Conditions

Backgrounds: The role of endothelial progenitor cells (EPCs) in angiogenesis is impaired in diabetes mellitus. The present study was conducted to observe the effects of nanopartikel green tea on the ability of EPCs exposed to high levels of glucose to release NO and induce endothelial cell migration. Purpose: This study aims to describe the mechanism of the role of green tea nanoparticles in increasing migration of endothelial cells in HUVEC cultures exposed to EPC-CM. The function of EPCs was assessed by evaluating HUVEC migration after administration of EPC-Conditioned Media. HUVEC migration was assessed by the Boyden chamber assay method. Method: Green Tea Nano Particles treatment at doses of 30 nM and 50 nM significantly increased endothelial cell migration at high glucose exposure of 22 mM. At a dose of 50 nM, normal glucose exposure increased endothelial cell migration better than high glucose exposure. Administration of high levels of glucose resulted in a decrease in the ability of EPCs to induce HUVEC migration, decrease in NO of EPCs, and decrease in the factor affecting EPC migration, namely SDF-1α and CXCR4. Results: Administration of 50 μM of nanopartikel green tea could inhibit the decreased ability of EPCs to induce HUVEC migration, and this effect was associated with NO, SDF-1α and CXCR4 concentrations. Conclusions: Administration of nanopartikel green tea could maintain the ability of EPCs exposed to high levels of glucose to release NO and induce HUVEC migration through an increase in SDF-1α and CXCR4.

Circulating ACE2 and the association of endothelial progenitor cell in CAD patients

Abstract Background/Introduction Angiotensin-converting enzyme (ACE) 2 is the homologue of ACE, and the local up-regulation of ACE2 expression associates to antiatherosclerosis. ACE2 hydrolyzes the angiogensin II, which related to impair of endothelial progenitor cell (EPC) function. EPCs maintain the integrity of vascular endothelium in case of damage. Decreased number of EPCs associate thrombosis. Purpose To investigate the circulating ACE2 and the link to EPC in CAD patients. Methods Data from 650 patients with stable angina pectoris requiring invasive coronary angiography were enrolled. They were divided into two groups according to the median value of ACE2. Two interventional cardiologists diagnosed obstructive CAD by angiography review. Demographic characteristics and clinical outcomes were compared between groups. Results In all subjects (median age 67 years, male=66.9%), a higher ACE2 level indicates elder, higher prevalence of hypertension, diabetes mellitus and chronic kidney disease. Significant EPC elevation when CAD numbers increased in higher ACE2 group (SVD vs. DVD vs. MVD = 0.005 vs. 0.006 vs. 0.007, p value=0.044). In multivariate analysis, higher ACE2 is positively correlated to triple vessel disease (TVD vs. no CAD, adjusted odds ratio=1.627, 95% CI 1.026-2.579). Conclusions Our data demonstrated higher circulation ACE2 links to EPCs in CAD patients.

Yiqihuoxue decoction (GSC) inhibits mitochondrial fission through the AMPK pathway to ameliorate EPCs senescence and optimize vascular aging transplantation regimens

BackgroundDuring the aging process, the number and functional activity of endothelial progenitor cells (EPCs) are impaired, leading to the unsatisfactory efficacy of transplantation. Previous studies demonstrated that Yiqihuoxue decoction (Ginseng-Sanqi-Chuanxiong, GSC) exerts anti-vascular aging effects. The purpose of this study is to evaluated the effects of GSC on D-galactose (D-gal)induced senescence and the underlying mechanisms.MethodsThe levels of cellular senescence-related markers P16, P21, P53, AMPK and p-AMPK were detected by Western blot analysis (WB). SA-β-gal staining was used to evaluate cell senescence. EPCs function was measured by CCK-8, Transwell cell migration and cell adhesion assay. The morphological changes of mitochondria were detected by confocal microscopy. The protein and mRNA expression of mitochondrial fusion fission Drp1, Mff, Fis1, Mfn1, Mfn2 and Opa1 in mitochondria were detect using WB and RT–qPCR. Mitochondrial membrane potential, mtROS and ATP of EPCs were measured using IF. H&E staining was used to observe the pathological changes and IMT of the aorta. The expressions of AGEs, MMP-2 and VEGF in aorta were measured using Immunohistochemical (IHC). The levels of SOD, MDA, NO and ET-1 in serum were detected by SOD, MDA and NO kits.ResultsIn vitro, GSC ameliorated the senescence of EPCs induced by D-gal and reduced the expression of P16, P21 and P53. The mitochondrial morphology of EPCs was restored, the expression of mitochondrial Drp1, Mff and Fis1 protein was decreased, the levels of mtROS and ATP were decreased, and mitochondrial function was improved. Meanwhile, the expression of AMPK and p-AMPK increased. The improvement effects of GSC on aging and mitochondrial morphology and function were were hindered after adding AMPK inhibitor. In vivo, GSC improved EPCs efficiency, ameliorated aortic structural disorder and decreased IMT in aging mice. The serum SOD level increased and MDA level decreased, indicating the improvement of antioxidant capacity. Increased NO content and ET-1 content suggested improvement of vascular endothelial function. The changes observed in SOD and MMP-2 suggested a reduction in vascular stiffness and the degree of vascular damage. The decreased expression of P21 and P53 indicates the delay of vascular senescence.

Astragaloside IV induces endothelial progenitor cell angiogenesis in deep venous thrombosis through inactivation of PI3K/AKT signaling.

Deep vein thrombosis (DVT), referred to as venous thromboembolism, is the third most frequent cardiovascular disease. Endothelial progenitor cells (EPCs) contribute to the recanalization of DVT. Astragaloside IV (AS-IV) has been suggested to have angiogenesis-enhancing effects. Here, we investigate the roles and mechanisms of AS-IV in EPCs and DVT. The experimental DVT model was established by inferior vena cava stenosis in rats. EPCs were collected from patients with DVT. Transwell assays were performed to detect cell migration. Tube formation was determined using Matrigel basement membrane matrix and ImageJ software. The thrombus weight and length were measured. Pathological changes were examined by hematoxylin-eosin staining. The production of proinflammatory cytokines was estimated by ELISA. The level of PI3K/AKT-related proteins was measured by western blotting. AS-IV administration facilitated the migrative and angiogenic functions of human EPCs in vitro. Additionally, AS-IV inhibited thrombosis and repressed the infiltration of leukocytes into the thrombus and the production of proinflammatory cytokines in rats. Mechanistically, AS-IV inactivated PI3K/AKT signaling in rats. AS-IV prevents thrombus in an experimental DVT model by facilitating EPC angiogenesis and decreasing inflammation through inactivation of PI3K/AKT signaling.

Thrombopoietin improves the functions of bone marrow endothelial progenitor cells via METTL16/Akt signalling of haematological patients with chemotherapy-induced thrombocytopenia.

Bone marrow endothelial progenitor cells (BM EPCs) are crucial in supporting haematopoietic regeneration, while the BM EPCs of haematological patients with chemotherapy-induced thrombocytopenia (CIT) are unavoidably damaged. Therefore, the present study aimed to examine the effect of thrombopoietin (TPO) on the recovery of BM EPCs of CIT patients and to identify the underlying mechanisms. The cell functions were determined by 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil)-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake and fluorescein isothiocyanate (FITC)-labeled Ulex europaeus agglutinin-I (FITC-UEA-I) binding assay, as well as proliferation, migration and tube formation experiments. Endothelial cells were transfected with METTL16 lentivirus, followed by methylated RNA immunoprecipitation sequencing. Zebrafish with vascular defect was used as the invivo model. TPO significantly improved the quantity and functions of BM EPCs from CIT patients invitro and restored the subintestinal vein area of zebrafish with vascular defect invivo. Mechanically, TPO enhanced the BM EPC functions through Akt signal mediated by METTL16, which was downregulated in BM EPCs of CIT patients and involved in the regulation of endothelial functions. The present study demonstrates that TPO improves the recovery of BM EPCs from CIT patients with haematological malignancies via METTL16/Akt signalling, which provides new insights into the role of TPO in treating CIT in addition to direct megakaryopoiesis.

Comorbidities and Angiogenic Regulators Affect Endothelial Progenitor Cell Subtype Numbers in a Healthy Volunteer Control Group.

Endothelial progenitor cells (EPCs) are stem cells that can repair injured blood vessels through neovascularisation. This is achieved through secretion of growth factors and endothelial maturation. EPC numbers and function have been studied to determine their diagnostic, prognostic and therapeutic potential in many ischaemic diseases such as stroke. However their activation homing and migration is not definitively understood in stroke patients. In this study, we profiled the non-stroke control group recruited into the Dunhill Medical Trust Endothelial Progenitor Cell Study. Demographic, clinical and plasma levels of angiogenic regulators of participants were analysed to determine if there was any correlation with EPC numbers, subtypes and function. Participants with diabetes had significantly supressed EPC numbers (CD45-CD34 + CD133 + KDR+) and CD34 + KDR + and KDR + EPC subtypes. Male participants had significantly lower EPC numbers compared to female participants and the proliferative capacity of endothelial colony forming cells significantly decreased with increasing participant age. Pro-angiogenic proteins such as granulocyte colony-stimulating factor and stromal cell-derived factor were positively correlated with both undifferentiated and endothelial-committed EPC subtype numbers (CD133+, KDR+, CD34 + CD133+, CD34 + KDR+), whereas anti-angiogenic proteins such as thrombospondin-1 showed a negative correlation with undifferentiated EPC subtypes (CD133+, CD34 + CD133+) but a positive correlation with endothelial-committed EPC subtype numbers (KDR+, CD34 + KDR+). These results show that EPC numbers and subtypes are affected by many factors and larger studies which can analyse and deconvolute the interactions between comorbidities, plasma biomarker levels and EPC are needed.

Senescence induces miR-409 to down-regulate CCL5 and impairs angiogenesis in endothelial progenitor cells.

This study explores the impact of senescence on autocrine C-C motif chemokine ligand 5 (CCL5) in human endothelial progenitor cell (EPCs), addressing the poorly understood decline in number and function of EPCs during ageing. We examined the effects of replication-induced senescence on CCL5/CCL5 receptor (CCR5) signalling and angiogenic activity of EPCs invitro and invivo. We also explored microRNAs controlling CCL5 secretion in senescent EPCs, its impact on EPC angiogenic activity, and validated our findings in humans. CCL5 secretion and CCR5 levels in senescent EPCs were reduced, leading to attenuated angiogenic activity. CCL5 enhanced EPC proliferation via the CCR5/AKT/P70S6K axis and increased vascular endothelial growth factor (VEGF) secretion. Up-regulation of miR-409 in senescent EPCs resulted in decreased CCL5 secretion, inhibiting the angiogenic activity, though these negative effects were counteracted by the addition of CCL5 and VEGF. In a mouse hind limb ischemia model, CCL5 improved the angiogenic activity of senescent EPCs. Analysis involving 62 healthy donors revealed a negative association between CCL5 levels, age and Framingham Risk Score. These findings propose CCL5 as a potential biomarker for detection of EPC senescence and cardiovascular risk assessment, suggesting its therapeutic potential for age-related cardiovascular disorders.

Novel cell therapy with ex vivo cultured peripheral blood mononuclear cells significantly impacts angiogenesis in the murine ischemic limb model

IntroductionAutologous mononuclear cells (MNCs) have been used in vascular regenerative therapy since the identification of endothelial progenitor cells (EPCs). However, the efficacy of autologous EPC therapy for diseases such as diabetes and connective tissue disorders is limited due to deficiencies in the number and function of EPCs. To address this, we developed a novel RE-01 cells that enriches pro-angiogenic cells from peripheral blood MNCs (PBMNCs). MethodsPBMNCs were collected from healthy volunteers following ethical guidelines. RE-01 cells were cultured in the presence of specific growth factors for 5 days without media change. Flow cytometry was used to analyze cell surface markers. Tube formation assays, EPC culture assays, and mRNA analysis were performed to evaluate angiogenic potential. The efficacy of RE-01 cells upon transplantation into ischemic hind limbs of mice was evaluated. ResultsRE-01 cells exhibited a significant increase in pro-angiogenic cells such as M2 macrophages and angiogenic T cells, in contrast to PBMNCs, while the number of inflammatory cells reduced. In vitro assays demonstrated the enhanced angiogenic abilities of RE-01 cells, supported by increased mRNA expression of angiogenesis-related cytokines. In vivo studies using mouse ischemic hind limb models have shown that blood flow and angiogenesis improved following RE-01 cell transplantation. Transplantations for 3 consecutive days significantly improved the number of pericyte-recruited vessels in the severely ischemic hind limbs of mice. ConclusionsRE-01 cells showed promising results in enhancing angiogenesis and arteriogenesis, possibly owing to the presence of M2 macrophages and angiogenic T cells. These cells also demonstrated anti-fibrotic effects. The efficacy of RE-01 cells has been confirmed in mouse models, suggesting their potential for treating ischemic vascular diseases. Clinical trials are planned to validate the safety and efficacy of RE-01 cell therapy in patients with connective tissue disease and unhealed ulcers. We hope that this new RE-01 cell therapy will prevent many patients from undergoing amputation.

Age-associated declined function of endothelial progenitor cells and its correlation with plasma IL-18 or IL-23 concentrations in patients with ST-segment elevation myocardial infarction

BackgroundST-segment elevation myocardial infarction (STEMI) persists to be prevalent in the elderly with a dismal prognosis. The capacity of endothelial progenitor cells (EPCs) is reduced with aging. Nevertheless, the influence of aging on the functionality of EPCs in STEMI is not fully understood.MethodThis study enrolled 20 younger STEMI patients and 21 older STEMI patients. We assessed the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events Risk (GRACE) scores in two groups. Then, we detected EPC migration, proliferation, adhesion, and plasma interleukin (IL)-18 and IL-23 concentrations in two groups. In addition, we analyzed the interconnection between age, EPC function, plasma IL-18 and IL-23 concentrations, and GRACE or TIMI scores in STEMI patients.ResultGRACE and TIMI scores in older STEMI patients were higher than in younger STEMI patients, whereas EPC function declined. GRACE and TIMI scores were found to have an inverse relationship with the EPC function. In older STEMI patients, plasma concentrations of IL-18 and IL-23 increased. Plasma IL-18 and IL-23 concentrations were adversely connected to EPC capacity and positively related to GRACE and TIMI scores. Moreover, age was positively correlated with plasma IL-18 or IL-23 concentrations, as well as GRACE or TIMI scores. However, age was adversely correlated with EPC function.ConclusionIn patients with STEMI, aging results in declined EPC function, which may be associated with inflammatory cytokines. The current investigation may offer new perception about mechanism and therapeutic targets of aging STEMI.

Dulaglutide restores endothelial progenitor cell levels in diabetic mice and mitigates high glucose-induced endothelial injury through SIRT1-mediated mitochondrial fission

Type 2 diabetes mellitus (T2DM) significantly impairs the functionality and number of endothelial progenitor cells (EPCs) and resident endothelial cells, critical for vascular repair and regeneration, exacerbating the risk of vascular complications. GLP-1 receptor agonists, like dulaglutide, have emerged as promising therapeutic agents due to their multifaceted effects, including the enhancement of EPC activity and protection of endothelial cells. This study investigates dulaglutide's effects on peripheral blood levels of CD34+ and CD133+ cells in a mouse model of lower limb ischemia and its protective mechanisms against high-glucose-induced damage in endothelial cells. Results demonstrated that dulaglutide significantly improves blood flow, reduces tissue damage and inflammation in ischemic limbs, and enhances glycemic control. Furthermore, dulaglutide alleviated high-glucose-induced endothelial cell damage, evident from improved tube formation, reduced reactive oxygen species accumulation, and restored endothelial junction integrity. Mechanistically, dulaglutide mitigated mitochondrial fission in endothelial cells under high-glucose conditions, partly through maintaining SIRT1 expression, which is crucial for mitochondrial dynamics. This study reveals the potential of dulaglutide as a therapeutic option for vascular complications in T2DM patients, highlighting its role in improving endothelial function and mitochondrial integrity.

The Effect of SGLT2 Inhibitor Therapy on Endothelial Progenitor Cell Function in Patients With Heart Failure.

Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to reduce the risk of cardiovascular mortality and hospitalizations in patients with heart failure (HF) with preserved or reduced ejection fraction (HFpEF or HFrEF). The mechanism for this benefit is not clear. Endothelial progenitor cells (EPCs) are bone marrow-derived cells able to differentiate into functional endothelial cells and participate in endothelial repair. The aim of this study was to evaluate the effect of SGLT-2 inhibitors on the level and function of EPCs in patients with HF. We enrolled 20 patients with symptomatic HF, 12 with HFrEF and 8 with HFpEF (aged 73.3 ± 10.2 years, 95% men). Blood samples were drawn at 2 time points: baseline and ≥3 months after initiation of SGLT-2 inhibitor therapy. Circulating EPC levels were evaluated by expression of vascular endothelial growth factor receptor-2 (VEGFR-2), CD34, and CD133 by flow cytometry. EPC colony forming units (CFUs) were quantified after 7 days in culture. The proportion of cells that coexpressed VEGFR-2 and CD34 or VEGFR-2 and CD133 was higher following 3 months of SGLT-2 inhibitors [0.26% (interquartile range, IQR 0.10-0.33) versus 0.55% (IQR 0.28-0.91), P = 0.002; 0.12% (IQR 0.07-0.15) versus 0.24% (IQR 0.15-0.39), P = 0.001, respectively]. EPC CFUs were also increased following SGLT-2 inhibitor treatment [23 (IQR 3.7-37.8) versus 79.4 (IQR 25.1-110.25) colonies/10 6 cells, P = 0.0039]. In patients with symptomatic HF, both HFpEF and HFrEF, treatment with SGLT-2 inhibitors is associated with an increase in the level and function of circulating EPCs. This augmentation in EPCs may be a contributing mechanism to the clinical benefit of SGLT-2 inhibitors in patients with HF.

Endothelial progenitor cells control remodeling of uterine spiral arteries for the establishment of utero-placental circulation

Placental ischemia, resulting from inadequate remodeling of uterine spiral arteries, is a factor in the development of preeclampsia. However, the effect of endothelial progenitor cells that play a role in the vascular injury-repair program is largely unexplored during remodeling. Here, we observe that preeclampsia-afflicted uterine spiral arteries transition to a synthetic phenotype in vascular smooth muscle cells and characterize the regulatory axis in endothelial progenitor cells during remodeling in human decidua basalis. Excessive sEng, secreted by AMP-activated protein kinase (AMPK)-deficient endothelial progenitor cells through the inhibition of HO-1, damages residual endothelium and leads to the accumulation of extracellular matrix produced by vascular smooth muscle cells during remodeling, which is further confirmed by animal models. Collectively, our findings suggest that the impaired functionality of endothelial progenitor cells contributes to the narrowing of remodeled uterine spiral arteries, leading to reduced utero-placental perfusion. This mechanism holds promise in elucidating the pathogenesis of preeclampsia.

Human Cord Blood Endothelial Progenitor Cells and Pregnancy Complications (Preeclampsia, Gestational Diabetes Mellitus, and Fetal Growth Restriction).

Hemangioblasts give rise to endothelial progenitor cells (EPCs), which also express the cell surface markers CD133 and c-kit. They may differentiate into the outgrowth endothelial cells (OECs) that control neovascularization in the developing embryo. According to numerous studies, reduced levels of EPCs in circulation have been linked to human cardiovascular disorders. Furthermore, preeclampsia and senescence have been linked to levels of EPCs produced from cord blood. Uncertainties surround how preeclampsia affects the way EPCs function. It is reasonable to speculate that preeclampsia may have an impact on the function of fetal EPCs during the in utero period; however, the present literature suggests that maternal vasculopathies, including preeclampsia, damage fetal circulation. Additionally, the differentiation potential and general activity of EPCs may serve as an indicator of the health of the fetal vascular system as they promote neovascularization and repair during pregnancy. Thus, the purpose of this review is to compare-through the assessment of their quantity, differentiation potency, angiogenic activity, and senescence-the angiogenic function of fetal EPCs obtained from cord blood for normal and pregnancy problems (preeclampsia, gestational diabetes mellitus, and fetal growth restriction). This will shed light on the relationship between the angiogenic function of fetal EPCs and pregnancy complications, which could have an effect on the management of long-term health issues like metabolic and cardiovascular disorders in offspring with abnormal vasculature development.

Progenitor Cell Function and Cardiovascular Remodelling Induced by SGLT2 Inhibitors.

Sodium-glucose cotransporters 2 (SGLT2) are high-capacity, low-affinity transporters, expressed mainly in the early portion of the proximal renal tube, mediating up to 90% of renal glucose uptake, while SGLT1 receptors are found mainly in the small intestine, facilitating glucose absorption. SGLT2 inhibitors (SGLT2i) originally emerged as agents for the treatment of type 2 diabetes mellitus; however, they soon demonstrated remarkable cardio- and renoprotective actions that led to their licensed use for the treatment of heart failure and chronic kidney disease, regardless of the diabetic status. Cardiovascular remodelling represents an umbrella term that encompasses changes that occur in the cardiovascular system, from the molecular and cellular level, to tissue and organs after local injury, chronic stress, or pressure. SGLT modulation has been shown to positively affect many of these molecular and cellular changes observed during pathological remodelling. Among the different pathophysiological mechanisms that contribute to adverse remodelling, various stem and progenitor cells have been shown to be involved, through alterations in their number or function. Recent studies have examined the effects of SGLT2i on stem and progenitor cell populations and more specifically on endothelial progenitor cells (EPCs). Although some found no significant effect, others showed that SGLT2i can modulate the morphology and function of EPCs. These preliminary observations of the effect of SGLT2i on EPCs may be responsible for some of the beneficial effects of gliflozins on pathological remodelling and, by extension, on cardiovascular disease. The purpose of this narrative review is to critically discuss recent evidence on the cardioprotective effects of SGLT2is, in the context of cardiac remodelling.

Transdermal Nicotine Patch Increases the Number and Function of Endothelial Progenitor Cells in Young Healthy Nonsmokers without Adverse Hemodynamic Effects.

Transdermal nicotine patches (TNPs), administering nicotine into the bloodstream through skin, have been widely used as nicotine replacement therapy, and exposure to nicotine can be detected by measurement of plasma cotinine concentration. In animal studies, nicotine treatment could increase the number of endothelial progenitor cells (EPCs), but the effect of TNPs on circulating EPCs and their activity in humans remained unclear. This study aimed to explore the influence of TNPs on circulating EPCs with surface markers of CD34, CD133, and/or KDR, and colony-forming function plus migration activity of early EPCs derived from cultured peripheral blood mononuclear cells before and after TNP treatments in young healthy nonsmokers. In parallel, pulse wave analysis (PWA) was applied to evaluate the vascular effect of TNP treatments. Twenty-one participants (25.8 ± 3.6 years old, 10 males) used TNP (nicotine: 4.2 mg/day) for 7 consecutive days. During the treatment, the CD34+ EPCs progressively increased in number. In addition, the number of EPCs positive for CD34/KDR, CD133, and CD34/CD133 were also increased on day 7 of the treatment. Furthermore, the early EPC colony-forming function and migration activity were increased with the plasma cotinine level positively correlating with change in colony-forming unit number. PWA analyses on day 7, compared with pretreatment, did not show significant change except diastolic pressure time index, which was prolonged and implied potential vascular benefit. In conclusion, 7-day TNP treatments could be a practical strategy to enhance angiogenesis of circulating EPCs to alleviate tissue ischemia without any hemodynamic concern.

C1q/Tumor Necrosis Factor-Related Protein-9 Is a Novel Vasculoprotective Cytokine That Restores High Glucose-Suppressed Endothelial Progenitor Cell Functions by Activating the Endothelial Nitric Oxide Synthase.

This study investigated whether gCTRP9 (globular C1q/tumor necrosis factor-related protein-9) could restore high-glucose (HG)-suppressed endothelial progenitor cell (EPC) functions by activating the endothelial nitric oxide synthase (eNOS). EPCs were treated with HG (25 mmol/L) and gCTRP9. Migration, adhesion, and tube formation assays were performed. Adiponectin receptor 1, adiponectin receptor 2, and N-cadherin expression and AMP-activated protein kinase, protein kinase B, and eNOS phosphorylation were measured by Western blotting. eNOS activity was determined using nitrite production measurement. Invivo reendothelialization and EPC homing assays were performed using Evans blue and immunofluorescence in mice. Treatment with gCTRP9 at physiological levels enhanced migration, adhesion, and tube formation of EPCs. gCTRP9 upregulated the phosphorylation of AMP-activated protein kinase, protein kinase B, and eNOS and increased nitrite production in a concentration-dependent manner. Exposure of EPCs to HG-attenuated EPC functions induced cellular senescence and decreased eNOS activity and nitric oxide synthesis; the effects of HG were reversed by gCTRP9. Protein kinase B knockdown inhibited eNOS phosphorylation but did not affect gCTRP9-induced AMP-activated protein kinase phosphorylation. HG impaired N-cadherin expression, but treatment with gCTRP9 restored N-cadherin expression after HG stimulation. gCTRP9 restored HG-impaired EPC functions through both adiponectin receptor 1 and N-cadherin-mediated AMP-activated protein kinase /protein kinase B/eNOS signaling. Nude mice that received EPCs treated with gCTRP9 under HG medium showed a significant enhancement of the reendothelialization capacity compared with those with EPCs incubated under HG conditions. CTRP9 promotes EPC migration, adhesion, and tube formation and restores these functions under HG conditions through eNOS-mediated signaling mechanisms. Therefore, CTRP9 modulation could eventually be used for vascular healing after injury.

Porphyromonas gingivalis GroEL exacerbates orthotopic allograft transplantation vasculopathy via impairment of endothelial cell function.

Orthotopic allograft transplantation (OAT) is a significant approach to addressing organ failure. However, persistent immune responses to the allograft affect chronic rejection, which induces OAT vasculopathy (OATV) and organ failure. Porphyromonas gingivalis can infiltrate remote organs via the bloodstream, thereby intensifying the severity of cardiovascular, respiratory, and neurodegenerative diseases and cancer. GroEL, a virulence factor of P. gingivalis promotes pro-inflammatory cytokine production in host cells, which assumes to play a pivotal role in the pathogenesis of cardiovascular diseases. Although the aggravation of OATV is attributable to numerous factors, the role of GroEL remains ambiguous. Therefore, this study aimed to investigate the impact of GroEL on OATV. Aortic grafts extracted from PVG/Seac rats were transplanted into ACI/NKyo rats and in vitro human endothelial progenitor cell (EPC) and coronary artery endothelial cell (HCAEC) models. The experimental findings revealed that GroEL exacerbates OATV in ACI/NKyo rats by affecting EPC and smooth muscle progenitor cell (SMPC) function and enabling the anomalous accumulation of collagen. In vitro, GroEL spurs endothelial-mesenchymal transition in EPCs, reduces HCAEC tube formation and barrier function by downregulating junction proteins, accelerates HCAEC aging by lowering mitochondrial membrane potential and respiratory function, and impedes HCAEC migration by modulating cytoskeleton-associated molecules. This study suggests that P. gingivalis GroEL could potentially augment OATV by impacting vascular progenitor and endothelial cell functions.

α7nAChR Activation Combined with Endothelial Progenitor Cell Transplantation Attenuates Lung Injury in Diabetic Rats with Sepsis through the NF-κB Pathway.

Chronic diabetes mellitus compromises the vascular system, which causes organ injury, including in the lung. Due to the strong compensatory ability of the lung, patients always exhibit subclinical symptoms. Once sepsis occurs, the degree of lung injury is more severe under hyperglycemic conditions. The α7 nicotinic acetylcholine receptor (α7nAChR) plays an important role in regulating inflammation and metabolism and can improve endothelial progenitor cell (EPC) functions. In the present study, lung injury caused by sepsis was compared between diabetic rats and normal rats. We also examined whether α7nAChR activation combined with EPC transplantation could ameliorate lung injury in diabetic sepsis rats. A type 2 diabetic model was induced in rats via a high-fat diet and streptozotocin. Then, a rat model of septic lung injury was established by intraperitoneal injection combined with endotracheal instillation of LPS. The oxygenation indices, wet-to-dry ratios, and histopathological scores of the lungs were tested after PNU282987 treatment and EPC transplantation. IL-6, IL-8, TNF-α, and IL-10 levels were measured. Caspase-3, Bax, Bcl-2, and phosphorylated NF-κB (p-NF-κB) levels were determined by blotting. Sepsis causes obvious lung injury, which is exacerbated by diabetic conditions. α7nAChR activation and endothelial progenitor cell transplantation reduced lung injury in diabetic sepsis rats, alleviating inflammation and decreasing apoptosis. This treatment was more effective when PNU282987 and endothelial progenitor cells were administered together. p-NF-κB levels decreased following treatment with PNU282987 and EPCs. In conclusion, α7nAChR activation combined with EPC transplantation can alleviate lung injury in diabetic sepsis rats through the NF-κB signaling pathway.

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.