Homing Of Endothelial Progenitor Cells Research Articles

The Role of Synthetic Extracellular Matrices in Endothelial Progenitor Cell Homing for Treatment of Vascular Disease.

Poor vascular homeostasis drives many clinical disorders including diabetes, arthritis, atherosclerosis, and peripheral artery disease. Local tissue ischemia resultant of insufficient blood flow is a potent stimulus for recruitment of endothelial progenitor cells (EPCs). This mobilization and homing is a multi-step process involving EPC detachment from their steady state bone marrow niches, entry into circulation, rolling along vessel endothelium, transmigration, and adhesion to denuded extracellular matrix (ECM) where they may participate in neovessel formation. However, these events are often interrupted in pathological conditions partly due to an imbalance in factor presentation at the tissue level. EPC number and function is impaired in patients with vascular diseases and this dysfunction has been proposed as a prominent contributor to disease pathogenesis. Research approaches aimed at providing therapeutic angiogenesis commonly involve the delivery of proangiogenic cells and/or soluble factors. Nevertheless, greater understanding of the mechanisms involved in EPC homing in both healthy and diseased states is critical for improving efficacy of such strategies. This review underscores the matrix-related signals necessary for enhancing EPC recruitment to ischemic tissue and provides an overview of the development of synthetic ECMs that aim to mimic functions of the local native microenvironment for use in therapeutic angiogenesis.

Autophagy protein 5 enhances the function of rat EPCs and promotes EPCs homing and thrombus recanalization via activating AKT

Deep venous thrombosis (DVT) is one of the most common peripheral vascular diseases. The roles of bone marrow-derived endothelial progenitor cells (EPCs) on the recanalization of venous thrombosis has been suggested recently, while the underlying mechanisms are not completely understood. Our objective was to investigate the functions of autophagy protein 5 (ATG5) in rat EPCs and its potential application in DVT. We have found that silencing of ATG5 or pharmacological suppression of ATG5 in rat EPCs reduces both the migration and psudotube formation under hypoxia in vitro. In line, overexpression of ATG5 significantly enhances the EPCs migration and psudotube formation capabilities. More importantly, injection of EPCs that stably express ATG5 increases EPC homing to the ischemic site and promotes thrombus recanalization in a rat DVT model in vivo. Mechanistically, we have shown that ATG5 overexpression enhances psudotube formation via the activation of AKT. These findings suggest that ATG5-AKT signaling plays an essential role in EPC migration and psudotube formation. Regulation of ATG5-AKT signaling may provide a potential novel therapy for DVT.

Abstract 231: Role of SDF-1α-induced Double Reciprocal E-Selectin/Ligand Pairs in Mediating Recruitment of Endothelial Progenitor Cells to Ischemic Wounds

Introduction: We previously reported that stromal cell-derived factor-1α (SDF-1α)-induced endothelial progenitor cells (EPC) homing is enhanced by up-regulation of E-selectin (E-sel) on luminal endothelial cells (EC) lining capillaries, locally within wound tissues. We now investigate how elevated SDF-1α in wounds achieves a remote effect on bone marrow-derived (BMD) circulating EPC. Methods: SDF-1α-induced cell adhesion molecules in human EPC and human microvascular endothelial cells (HMVEC) were profiled using PCR-Array and validated by immunoblot. Induction of E-sel expression on murine BMD- and circulating EPC by SDF-1α was examined by flow cytometry. The involvement of E-sel/ligand in mediating SDF-1α-induced EPC-EC interaction and EPC transendothelial migration was studied using in vitro EPC-EC binding assay. The role of SDF-1α-induced E-sel in regulating EPC homing, wound neovascularization and healing were furthered studied by testing EPC from ROSA26-LacZ+/E-sel -/- versus ROSA26-LacZ+/E-sel +/+ mice in an ischemic wound model. Results: SDF-1α enhanced EPC-EC interaction by upregulating expression of E-sel/ligand in human EPC and HMVEC. Administration of SDF-1α in wound also increased E-sel expression on BMD- and circulating EPC in mice. The effects of SDF-1α on EPC-EC interaction and EPC transendothelial migration were specifically mediated by E-sel, as E-sel antagonists could inhibit these processes. E-sel was required for SDF-1α-induced EPC homing, wound neovascularization and healing in vivo (n=6, P<0.05). Conclusions: EPC-EC interaction is an essential process for EPC homing. SDF-1α induces both local luminal EC lining capillaries in wound tissue and remote BMD- and circulating EPC to express E-sel and its ligands. Up-regulated E-sel/ligand pairs reciprocally on EC and EPC serve as “Double-Lock” to secure targeted EPC-EC interactions selectively occurring within wound endothelium. These findings uncover a novel mechanism underlying the pro-angiogenic effect of SDF-1α on EPC homing and point to E-sel/ligand pairs reciprocally induced on circulating EPC and local endothelium as effective targets for ex vivo manipulation and therapeutic neovascularization.

Abstract 438: Regulation of Ischemia-induced Neovascularization by 20-HETE Involves Bone Marrow-derived EPC.

Objective: Compensatory neovascularization is an important adaptation for recovery from critical ischemia. The CYP4A-derived 20-HETE were recently identified as a novel regulator of angiogenesis. Here, we assessed the contribution of 20-HETE to ischemia-induced neovascularization and its underlying molecular and cellular mechanisms. Methods: The mouse ischemia hindlimb angiogenesis assay was established to study the role of CYP4A-20-HETE in compensatory angiogenesis using the 20-HETE synthase inhibitor (DDMS, 10mg/kg/d) and the 20-HETE antagonist (6, 15-20-HEDGE, 10mg/kg/d). Hindlimb blood flow and microvessels density in ischemic hindlimb muscle were measured by Laser Doppler Perfusion Imaging and Immunofluorescent staining, respectively. 20-HETE production in ischemic muscles was measured by LC-MS-MS. Western blot was performed to explore the underlying signaling pathways. Flow cytometry analysis was used to assess the contribution of 20-HETE to mobilization and homing of bone marrow (BM)-derived endothelial progenitor cells (EPC) to ischemic neovascularization. Results: 20-HETE inhibition by DDMS and 6, 15-20-HEDGE reduced the blood flow perfusion and microvessel formation in response to ischemia by 46±2.3% and 34±1.2%, respectively. Importantly, ischemic hindlimb muscles showed markedly elevated 20-HETE synthesis compared to non-ischemic controls (96 ± 17 pg/mg protein vs. non-detectable). HIF-1α, VEGF, and VEGFR2 expression were markedly induced in ischemic hindlimb muscles, but were negated by DDMS and 6, 15-20-HEDGE. Furthermore, ischemia induced BM-derived EPC mobilization and subsequent EPC homing to the ischemic hindlimb muscle by 5.5±0.7 and 20±2.8 folds, respectively, whereas DDMS and 6, 15-20-HEDGE significantly attenuated these processes. Conclusions: An increase in 20-HETE production in ischemic muscles regulates ischemic compensatory neovascularization via the induction of the HIF-1α/VEGF pathways that support the mobilization and homing of BM-derived EPC. These results strengthen the notion that 20-HETE is a key regulator of ischemic compensatory angiogenesis via regulation of EPC function and may represent a novel therapeutic target.

Interaction of platelets with endothelial progenitor cells in the experimental atherosclerosis: Role of transplanted endothelial progenitor cells and platelet microparticles.

Recent studies suggest that endothelial progenitor cells (EPCs) and platelets have an important role in repair following vascular injury. Although evidence suggest that platelets are essential in EPC attracting, homing and differentiation to the injury site; however, the platelet effects on EPC function in atherosclerosis have received less attention. In this context, we followed the consequences of circulating EPCs and platelet microparticles (PMPs) administration on platelet-EPC interaction in atherosclerosis and the involved mechanisms. The experiments were performed on Golden Syrian hamsters divided in five equal groups: control (C), hypertensive-hypercholesterolemic (HH), HH treated with EPCs (HH-EPCs) or PMPs (HH-PMPs) and HH treated with EPCs and PMPs (HH-EPCs-PMPs). Compared with C group, EPCs isolated from HH and HH-PMPs groups presented a reduction of endothelial nitric oxide synthase and vascular endothelial growth factor expressions and an increase in thrombospondin-1 expression and inflammatory molecule secretion: interleukin 8 (IL)-8, myeloperoxidase (MPO) and plasminogen activator inhibitor-1 (PAI-1). EPC administration had beneficial effects, the obtained results being similar with those from the C group, while the combination with PMPs did not improve the EPC influences. Static coincubation of EPCs from HH and HH-PMPs with analogous platelets resulted in an increased EPC adhesion/migration, and IL-8, monocyte chemotactic protein-1, regulated on activation, normal T expressed and secreted, MPO and PAI-1 release, explained by the platelet hyperaggregability induced by pronounced distribution of vasodilator-stimulated phosphoprotein and filamentous actin, and the secretion of proinflammatory factors: IL-1β, -6, -8, CD40 ligand. EPC therapy alone revealed an impaired platelet-EPC interaction directly correlated with the reduction of inflammatory markers and platelet aggregability. Moreover, in a dynamic flow system, EPCs and platelets from HH and HH-PMPs exhibited weakened interplay abilities, while EPC transplantation reinforces them. The present study demonstrates that HH animals revealed functional impairment of EPCs and platelets, which correlate with their reduced contribution to re-endothelialisation at the injury site, although in vitro exposure to immobilised platelets promotes their adhesion and migration. EPC administration alone recovers EPC/platelet functions and consolidates their interaction under dynamic flow conditions. These findings disclose new advances in understanding the platelet-EPC interaction and its role in the vascular repair.

Effects of pneumoperitoneum preconditioning on endothelial progenitor cells and renal protective mechanism in rats

To explore the pneumoperitoneum-mediated renoprotective effects of preconditioning, mobilizing and homing of endothelial progenitor cells (EPCs) in rats. A total of 40 rats were randomized by a numerical table into 5 groups of gasless (C), pneumoperitoneum injury (Pp), long-term pneumoperitoneum preconditioning (P-L), mid-term pneumoperitoneum preconditioning (P-M) and short-term pneumoperitoneum preconditioning (P-S). C group had a pneumoperitoneum pressure of 0 mmHg; Pp group 15 mmHg, time 60 min; P-L, P-M, P-S groups were deflated and deflated preconditioning before pneumoperitoneum, then the same as Pp group, P-L group: inflation time was 25 min, gas discharge time 10 min; P-M group: 15 min, 10 min; P-S group: 5 min, 10 min. At 24 h post-operation, the animals were sacrificed by destroying cervical spine. And the specimens of venous blood and kidneys were harvested. Also the extent of renal injury, the homing of EPCs, the proliferation and angiogenesis of renal endothelial cell and the expression of angiogenic growth factor were analyzed. Compared with Pp group, P-L, P-M and P-S groups exhibited significant improvements in renal function, morphology and histological score (1.88 ± 0.35, 1.63 ± 0.52, 1.75 ± 0.46 vs 2.38 ± 0.52, all P < 0.05). The histological scores of P-M and P-S groups improved significantly versus P-L group (both P < 0.05). P-M and P-S groups showed no significant difference in histological score (P > 0.05). The number of EPCs in kidneys increased in P-L, P-M and P-S groups versus Pp group (2.18% ± 0.14%, 2.87% ± 0.29%, 2.90% ± 0.24% vs 1.73% ± 0.19%, all P < 0.05). The EPCs numbers of P-M and P-S groups were more than that of P-L group (both P < 0.05). And no significant difference existed between P-M and P-S groups (P > 0.05). Compared with Pp group, EPCs of P-L, P-M and P-S groups markedly increased in kidneys. No significant difference existed between P-M and P-S groups, but P-L group was the lowest. Also there was an up-regulated expression of stromal cell derived factor 1-α in pretreated kidneys versus Pp group (all P < 0.05). And P-M and P-S groups increased markedly. Pneumoperitoneum-mediated preconditioning protects against kidney injury by promoting EPC homing and enhancing endothelial cell and vascular proliferations. And short and medium-term preconditioning protocols are more effective for protecting kidneys.

Maintaining Moderate Platelet Aggregation and Improving Metabolism of Endothelial Progenitor Cells Increase the Patency Rate of Tissue-Engineered Blood Vessels.

Small-diameter tissue-engineered blood vessels (TEBVs) have been associated with low, long-term patency rates primarily because of acute thrombosis in early stages and an inability to achieve early endothelialization. Platelets and endothelial progenitor cells (EPCs) play a key role in these processes. A nano delayed-release 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR)-bound TEBV was implanted in rat carotid arteries for 3 months. AICAR-bound TEBVs had a high patency rate compared with control TEBVs after 3 months. We found that AICAR maintained moderate platelet aggregation in vivo. In vitro data indicated that AICAR inhibits the release of 5-hydroxytryptamine and thromboxane A2 in activating platelets to reduce platelet aggregation. Then, we confirmed that AICAR strengthens the EPC energy state, which results in earlier endothelialization. The homing, migration, and paracrine function of EPCs were enhanced by AICAR in vitro. Besides, AICAR can contribute to the migration of endothelial cells near the anastomosis. The cellularization of TEBVs at different time points was observed too. In conclusion, our study suggests that the application of nanodelivery material containing AICAR can effectively improve small-diameter TEBVs by maintaining moderate platelet aggregation and improving metabolism of EPCs.

Transplantation of cryopreserved human umbilical cord blood-derived endothelial progenitor cells induces recovery of carotid artery injury in nude rats

IntroductionTransplantation of endothelial progenitor cells (EPCs) restores endothelial function in patients with endothelial dysfunction and initial denudation. The goal of the present study was to determine the effect of cryopreserved human umbilical cord blood (UCB)-derived EPC infusion on the repair of carotid artery injury in nude rats.MethodsMononuclear cells (MNCs) from human cryopreserved UCB and peripheral blood (PB) of patients with cardiovascular diseases and healthy volunteers were cultured in a conditioned medium. The in vitro migration, proliferation, adhesion, and survival capacities, as well as paracrine cytokine release of EPCs were investigated. EPC homing, induced reendothelialization, and the effect on neointima formation were also assessed in vivo.ResultsPatient-derived PB EPCs (PPB-EPCs) displayed decreased migration, proliferation, adhesion, and survival capabilities as compared to PB-EPCs from healthy volunteers (HPB-EPCs) and cryopreserved UCB-EPCs. However, there was no difference in the release of vascular endothelial growth factor (VEGF) and stromal cell derived factor 1 (SDF-1) between the three groups. Two weeks after transplantation, more labeled UCB-EPCs and HPB-EPCs than PPB-EPCs were found by cell tracking in the injury zone. Administration of PPB-EPCs, HPB-EPCs, and UCB-EPCs enhanced reendothelialization and inhibited neointima formation compared to the saline control. However, UCB-EPC and HPB-EPC infusion showed a greater improvement than PPB-EPCs.ConclusionsCryopreserved UCB-MNCs derived EPCs and HPB-EPCs show better responses to cytokines and vascular injury than PPB-EPCs. Thus, cryopreservation and delivery of cryopreserved autogenous UCB-EPCs or HPB-EPCs may be a promising vasculoprotective approach for patients with multiple cardiovascular risk factors.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0022-4) contains supplementary material, which is available to authorized users.

The expression of P2X7 receptors in EPCs and their potential role in the targeting of EPCs to brain gliomas

In order to use endothelial progenitor cells (EPCs) as a therapeutic and imaging probe to overcome antiangiogenic resistance for gliomas, how to enhance proliferation and targeting ability of transplanted EPCs is a high priority. Here, we confirmed, for the first time, the expression of P2X7 receptors in rat spleen-derived EPCs. Activation of P2X7 receptors in EPCs by BzATP promoted cells proliferation and migration, rather than apoptosis. In vivo, the homing of transplanted EPCs after long-term suppression of P2X7 receptors by persistent BBG stimulation was evaluated by MRI, immunohistochemistry and flow cytometry. Compared to the group without BBG treatment, less transplanted EPCs homed to gliomas in the group with BBG treatment, especially integrated into the vessels containing tumor-derived endothelial cells in gliomas. Moreover, western blot showed that CXCL1 expression was downregulated in gliomas with BBG treatment, which meant P2X7 receptors suppression inhibited the homing of EPCs to gliomas through down-regulation of CXCLl expression. Further, effects of P2X7 receptors on C6 glioma cells or gliomas were evaluated at the same dose of BzATP or BBG used in EPCs experiments in vitro and in vivo. MTT assay and MRI revealed that P2X7 receptors exerted no significant promoting effect on C6 glioma cells proliferation, gliomas growth and angiogenesis. Taken together, our findings imply the possibility of promoting proliferation and targeting ability of transplanted EPCs to brain gliomas in vivo through P2X7 receptors, which may provide new perspectives on application of EPCs as a therapeutic and imaging probe to overcome antiangiogenic resistance for gliomas.

Resistin promotes angiogenesis in endothelial progenitor cells through inhibition of microRNA‐206

Resistin has a proinflammatory function in human that contributes to the link between inflammation and cardiovascular disease and is also associated with rheumatoid arthritis (RA).The aim of this study was to examine the potential function ofresistin in human circulating endothelial progenitor cells (EPCs) during angiogenesis in RA.EPCs isolated from healthy donors were used to investigate the mechanisms underlying EPCs migration and tube formation. In addition, potential microRNA‐206 (miR‐206) targets were validated using real‐time quantitative polymerase chain reaction, western blotting, and a luciferase reporter assay. Resistin is highly expressed in synovial fluids and tissues in RA patients and mice with collagen‐induced arthritis and promotes both EPC homing to synovia and angiogenesis. We show that resistin directly induces significant upregulation of vascular endothelial growth factor (VEGF) expression in EPCs and promotes expression of the VEGF 3ʹ untranslated region in the absence of a miR‐206 binding site. Our study is the first to demonstrate that a signaling pathway involving miR‐206 is involved in resistin‐induced VEGF expression and that EPCs migrate into RA joints in vitro and in vivo; these results provide support for resistin as a therapeutic target of RA.

Altered chemokine signalling in endothelial progenitor cells from acute ulcerative colitis patients.

Ulcerative colitis (UC) is a chronic, idiopathic, inflammatory bowel disease, characterized by alternating stages of clinically active and inactive disease. UC exhibits several inflammatory characteristics, including immune activation, leukocyte infiltration, and altered vascular density. In UC, many of the upregulated inflammatory cytokines are proangiogenic and are released by diverse cell populations, such as infiltrating immune cells and endothelial cells (EC). Increasing evidences suggest that neovascularisation may involve also endothelial progenitor cells (EPCs). In this study we evaluated EPCs recruitment and homing, assessed by CXCR4 expression, in both acute and remitting phase of UC. We report an overall decrease of EPCs in UC patients (controls = 97,94 ± 37,34 cells/mL; acute = 31,10 ± 25,38 cells/mL; remitting = 30,33 ± 19,02 cells/mL; P < 0.001 for both UC groups versus controls). Moreover CXCR4+-EPCs, committed to home in inflammatory conditions, were found to be reduced in acute UC patients compared to both remitting patients and controls (acute = 3,13 ± 4,61 cells/mL; controls = 20,12 ± 14,0; remitting = 19,47 ± 12,83; P < 0,001). Interestingly, we found that administration of anti-inflammatory drugs in acute UC is associated with an increase in circulating EPCs, suggesting that this therapy may exert a strong influence on the progenitor cells response to inflammatory processes.

A critical role of CXCR2 PDZ-mediated interactions in endothelial progenitor cell homing and angiogenesis

Bone marrow-derived endothelial progenitor cells (EPCs) contribute to neovessel formation in response to growth factors, cytokines, and chemokines. Chemokine receptor CXCR2 and its cognate ligands are reported to mediate EPC recruitment and angiogenesis. CXCR2 possesses a consensus PSD-95/DlgA/ZO-1 (PDZ) motif which has been reported to modulate cellular signaling and functions. Here we examined the potential role of the PDZ motif in CXCR2-mediated EPC motility and angiogenesis. We observed that exogenous CXCR2 C-tail significantly inhibited in vitro EPC migratory responses and angiogenic activities, as well as in vivo EPC angiogenesis. However, the CXCR2 C-tail that lacks the PDZ motif (ΔTTL) did not cause any significant changes of these functions in EPCs. In addition, using biochemical assays, we demonstrated that the PDZ scaffold protein NHERF1 specifically interacted with CXCR2 and its downstream effector, PLC-β3, in EPCs. This suggests that NHERF1 might cluster CXCR2 and its relevant signaling molecules into a macromolecular signaling complex modulating EPC cellular functions. Taken together, our data revealed a critical role of a PDZ-based CXCR2 macromolecular complex in EPC homing and angiogenesis, suggesting that targeting this complex might be a novel and effective strategy to treat angiogenesis-dependent diseases.

Angiogenesis in gastric mucosa: an important component of gastric erosion and ulcer healing and its impairment in aging.

Angiogenesis (also referred to as neovascularization-formation of new blood vessels from existing vessels) is a fundamental process essential for healing of tissue injury and ulcers because regeneration of blood microvessels is a critical requirement for oxygen and nutrient delivery to the healing site. This review article updates the current views on angiogenesis in gastric mucosa following injury and during ulcer healing, its sequential events, the underlying mechanisms, and the impairment of angiogenesis in aging gastric mucosa. We focus on the time sequence and ultrastructural features of angiogenesis, hypoxia as a trigger, role of vascular endothelial growth factor signaling (VEGF), serum response factor, Cox2 and prostaglandins, nitric oxide, and importin. Recent reports indicate that gastric mucosa of aging humans and experimental animals exhibits increased susceptibility to injury and delayed healing. Gastric mucosa of aging rats has increased susceptibility to injury by a variety of damaging agents such as ethanol, aspirin, and other non-steroidal anti-inflammatory drugs because of structural and functional abnormalities including: reduced gastric mucosal blood flow, hypoxia, reduced expression of vascular endothelial growth factor and survivin, and increased expression of early growth response protein 1 (egr-1) and phosphatase and tensin homolog (PTEN). Until recently, postnatal neovascularization was assumed to occur solely through angiogenesis sprouting of endothelial cells and formation of new blood vessels from pre-existing blood vessels. New studies in the last decade have challenged this paradigm and indicate that in some tissues, including gastric mucosa, the homing of bone marrow-derived endothelial progenitor cells to the site of injury can also contribute to neovascularization by a process termed vasculogenesis.

Processing of CXCL12 impedes the recruitment of endothelial progenitor cells in diabetic wound healing.

High blood sugar levels result in defective wound healing processes in diabetic patients. Endothelial progenitor cells (EPCs) play an important role in vasculogenesis, and thereby contribute to reconstitution of the microcirculation and healing. This study aimed to determine the possible mechanism by which the numbers of circulating EPCs are regulated in response to tissue wounding. In the streptozotocin-induced diabetic mouse model, we found that phagocytes activated by local inflammatory cytokines in the wound interfere with the mobilization and recruitment of EPCs to the lesion area. Specifically, the activated macrophages inactivate CXCL12, the major chemokine for EPC recruitment, via matrix metalloproteinases (MMPs), and thereby prevent local chemotaxis and subsequent homing of EPCs to the wound. The wound healing process is delayed by local administration of inflammatory cytokines, and its rate is increased by MMP inhibitors. This study indicates that local inhibition of MMPs is beneficial for regeneration of damaged vessels, and may explain poor wound healing in diabetic patients, thus demonstrating its potential utility as a local treatment therapy to promote diabetic wound healing.

Role of formyl peptide receptor 2 in homing of endothelial progenitor cells and therapeutic angiogenesis.

Endothelial progenitor cells (EPCs) hold a great promise as a therapeutic mediator in treatment of ischemic disease conditions. The discovery of EPCs in adult blood has been a cause of significant enthusiasm in the field of endothelial cell research and numerous clinical trials have been expedited. After more than a decade of research in basic science and clinical applications, limitations and new strategies of EPC therapeutics have emerged. With various phenotypes, vague definitions, and uncertain distinction from hematopoietic cells, understanding EPC biology remains challenging. However, EPCs, still hold great hope for treatment of critical ischemic injury as low concern regarding safety can accelerate the clinical applications from basic findings. This review provides an introduction to EPC as cellular therapeutics, which highlights a recent finding that EPC homing was promoted through FPR2 signaling.

Endothelial Progenitor Cell Homing Decreases Postoperative Complications in Patients Undergoing Cardiac Surgery with Cardiopulmonary Bypass

Background: Endothelial progenitor cells (EPCs) play an important role in tissue repair, however, their role in reducing complications of cardiac surgery is unclear. This study evaluated the effect of EPCs on cardiac surgery outcomes.Methods: The prospective, cohort, single central study was conducted in 127 rheumatic heart patients who received valve replacement with cardiopulmonary bypass from June 2009 to June 2011. Circulating EPCs were evaluated perioperatively. Composite surgical outcome was examined during hospital stays.Results: EPC counts decreased from 42 cells/ml before surgery to 12 cells/ml 4 hours after surgery, although granulocyte colony-stimulating factor significantly increased. The incidence of death, acute respiratory distress syndrome (ARDS), acute renal dysfunction, heart failure occurred less in high EPC homing group (0%, 47.6%, 0%, 0%) than in medium (2.38%, 50%, 2.38%, 2.38%) and low (2.33%, 69.8%, 6.98%, 6.98%) groups. Composite outcome events were also lower in high EPC homing group (P=0.000). Multivariate analysis showed the occurrence of composite outcome events and ARDS was still significantly different among the 3 groups (P=0.007 and P=0.042 respectively). Similarly, the higher pre-surgery EPC was associated with a lower incidence of composite outcome events (P=0.004).Conclusions: EPC homing occurs during early stages after cardiac surgery, and may help to reduce complications. Citation: Lei Du, Wen-Tong Meng, Yu-Jing Zhang, Jie Zhang, Jing Zhou, Jerry Yu, et al. Endothelial progenitor cell homing decreases postoperative complications in patients undergoing cardiac surgery with cardiopulmonary bypass. J Anesth Perioper Med 2014; 1: 15-24. doi: 10.24015/JAPM.2014.0004 This is an open-access article, published by Evidence Based Communications (EBC). This work is licensed under the Creative Commons Attribution 4.0 International License, which permits unrestricted use, distribution, and reproduction in any medium or format for any lawful purpose. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Stromal cell-derived factor-1-3'A polymorphism is associated with decreased risk of myocardial infarction and early endothelial disturbance.

Genome-wide association studies have identified single-nucleotide polymorphisms at the 10q11 locus as risk factors for myocardial infarction (MI). This locus lies upstream (∼80 kb) of the stromal cell-derived factor-1 (SDF1) gene that codify for a chemokine with protective atherogenetic effects and with a major role in the mobilization, homing, and differentiation of endothelial progenitor cells (EPCs). The purpose of this study was to investigate the possible association of SDF1-3'A polymorphism, that upregulates SDF1 protein expression, with MI and early endothelial dysfunction and atherosclerosis in young healthy subjects. 200 patients (181 men age 57.3 ± 7.7 years) and 230 healthy controls (96 men, age 52 ± 11.9 years) were recruited to investigate the association between MI and SDF1-3'A polymorphism. The relationship between SDF1-3'A polymorphism and brachial artery flow-mediated dilation and the number of circulating EPCs was examined in 50 healthy young adults. A significant difference in SDF1-3'A genotype distribution was observed between patients and controls (P = 0.006). Patients carrying the A allele had a significantly reduced MI risk compared with subjects with GG genotype (odds ratio = 0.5, 95% CI = 0.3-0.9, P = 0.001). SDF1-3'A polymorphism presented a significant interaction with other cardiovascular risk factors (Pinteraction < 0. 0001). Controls carrying the A allele showed significantly higher flow-mediated dilation (13.9 ± 4.9 vs 10.8 ± 4.3, P = 0.03) and significantly higher values of EPCs (0.029 ± 0.009 vs 0.022 ± 0.008, P = 0.02) compared with GG homozygotes. SDF1-3'A polymorphism is associated with a decreased risk of MI and early endothelial dysfunction, strongly confirming the important atherogenic role of SDF1 gene at clinical level.

The acute exposure effects of inhaled nickel nanoparticles on murine endothelial progenitor cells

Introduction: The discovery of endothelial progenitor cells (EPCs) may help to explain observed cardiovascular effects associated with inhaled nickel nanoparticle exposures, such as increases in vascular inflammation, generation of reactive oxygen species, altered vasomotor tone and potentiated atherosclerosis in murine species.Methods: Following an acute whole body inhalation exposure to 500 µg/m3 of nickel nanoparticles for 5 h, bone marrow EPCs from C57BL/6 mice were isolated. EPCs were harvested for their RNA or used in a variety of assays including chemotaxis, tube formation and proliferation. Gene expression was assessed for important receptors involved in EPC mobilization and homing using RT-PCR methods. EPCs, circulating endothelial progenitor cells (CEPCs), circulating endothelial cells (CECs) and endothelial microparticles (EMPs) were quantified on a BD FACSCalibur to examine endothelial damage and repair associated with the exposure.Results and conclusions: Acute exposure to inhaled nickel nanoparticles significantly increased both bone marrow EPCs as well as their levels in circulation (CEPCs). CECs were significantly elevated indicating that endothelial damage occurred due to the exposure. There was no significant difference in EMPs between the two groups. Tube formation and chemotaxis, but not proliferation, of bone marrow EPCs was impaired in the nickel nanoparticle exposed group. These results coincided with a decrease in the mRNA of receptors involved in EPC mobilization and homing. These data provide new insight into how an acute nickel nanoparticle exposure to half of the current Occupational Safety & Health Administration (OSHA) permissible exposure limit may adversely affect EPCs and exacerbate cardiovascular disease states.

Preserved function of late-outgrowth endothelial cells in medically treated hypertensive patients under well-controlled conditions.

Endothelial progenitor cells (EPCs) participate in renal repair, but their number and function may be impaired by exposure to cardiovascular risk factors. The number of circulating EPCs is decreased in essential and renovascular hypertensive patients, but the effects of hypertension on EPC function are incompletely understood. We hypothesized that EPC function was preserved under well-controlled conditions in treated hypertensive patients. Patients with atherosclerotic renal artery stenosis (ARAS; n=22) or essential hypertension (n=24) were studied during controlled sodium intake and antihypertensive regimen. Late-outgrowth EPCs were isolated from the inferior vena cava (IVC) and renal vein blood of ARAS and essential hypertension patients and a peripheral vein of matched normotensive controls (n=18). The angiogenic function of EPCs was assessed in vitro, and multidetector computed tomography was used to measure single-kidney hemodynamics and function in ARAS and essential hypertension patients. Inflammatory biomarkers and EPC homing signal levels and renal release were calculated. Inferior vena cava and renal vein-obtained EPC function were similar in ARAS and essential hypertension patients and comparable to that in normal controls (tube length, 171.86±16.846, 191.09±14.222, 174.925±19.774 μm, respectively). Function of renal vein-obtained EPCs directly correlated with stenotic kidney glomerular filtration rate, EPC homing factors, and anti-inflammatory mediator levels in ARAS patients. Therefore, EPC function was relatively preserved in ARAS patients, although it directly correlated with renal function. Adequate EPC function supports the feasibility of using autologous EPCs as a therapeutic option in essential and renovascular hypertensive patients. Homing signals and inflammatory mediators may potentially regulate EPC angiogenic function.

Systemic influences contribute to prolonged microvascular rarefaction after brain irradiation: a role for endothelial progenitor cells.

Whole brain radiation therapy (WBRT) induces profound cerebral microvascular rarefaction throughout the hippocampus. Despite the vascular loss and localized cerebral hypoxia, angiogenesis fails to occur, which subsequently induces long-term deficits in learning and memory. The mechanisms underlying the absence of vessel recovery after WBRT are unknown. We tested the hypotheses that vascular recovery fails to occur under control conditions as a result of loss of angiogenic drive in the circulation, chronic tissue inflammation, and/or impaired endothelial cell production/recruitment. We also tested whether systemic hypoxia, which is known to promote vascular recovery, reverses these chronic changes in inflammation and endothelial cell production/recruitment. Ten-week-old C57BL/6 mice were subjected to a clinical series of fractionated WBRT: 4.5-Gy fractions 2 times/wk for 4 wk. Plasma from radiated mice increased in vitro endothelial cell proliferation and adhesion compared with plasma from control mice, indicating that WBRT did not suppress the proangiogenic drive. Analysis of cytokine levels within the hippocampus revealed that IL-10 and IL-12(p40) were significantly increased 1 mo after WBRT; however, systemic hypoxia did not reduce these inflammatory markers. Enumeration of endothelial progenitor cells (EPCs) in the bone marrow and circulation indicated that WBRT reduced EPC production, which was restored with systemic hypoxia. Furthermore, using a bone marrow transplantation model, we determined that bone marrow-derived endothelial-like cells home to the hippocampus after systemic hypoxia. Thus, the loss of production and homing of EPCs have an important role in the prolonged vascular rarefaction after WBRT.