Homing Of Endothelial Progenitor Cells Research Articles

The construction of tissue-engineered blood vessels crosslinked with adenosine-loaded chitosan/β-cyclodextrin nanoparticles using a layer-by-layer assembly method.

A tissue-engineered blood vessel (TEBV) modified with CS/β-CD nanoparticles is constructed, effectively controling the release of adenosine, and this type of TEBV can keep open for over 6 months. This study also demonstrates for the first time that adenosine promotes endothelial progenitor cell (EPC) mobilization and homing via energy conversion, achieving rapid endothelialization of TEBV.

Endothelial Remodelling and Intracellular Calcium Machinery

Rather being an inert barrier between vessel lumen and surrounding tissues, vascular endothelium plays a key role in the maintenance of cardiovascular homeostasis. The de-endothelialization of blood vessels is regarded as the early event that results in the onset of severe vascular disorders, including atherosclerosis, acute myocardial infarction, brain stroke, and aortic aneurysm. Restoration of the endothelial lining may be accomplished by the activation of neighbouring endothelial cells (ECs) freed by contact inhibition and by circulating endothelial progenitor cells (EPCs). Intracellular Ca(2+) signalling is essential to promote wound healing: however, the molecular underpinnings of the Ca(2+) response to injury are yet to be fully elucidated. Similarly, the components of the Ca(2+) toolkit that drive EPC incorporation into denuded vessels are far from being fully elucidated. The present review will survey the current knowledge on the role of Ca(2+) signalling in endothelial repair and in EPC activation. We propose that endothelial regeneration might be boosted by intraluminal release of specific Ca(2+) channel agonists or by gene transfer strategies aiming to enhance the expression of the most suitable Ca(2+) channels at the wound site. In this view, connexin (Cx) channels/hemichannels and store-operated Ca(2+) entry (SOCE) stand amid the most proper routes to therapeutically induce the regrowth of denuded vessels. Cx stimulation might trigger the proliferative and migratory behaviour of ECs facing the lesion site, whereas activation of SOCE is likely to favour EPC homing to the wounded vessel.

PPARα regulates mobilization and homing of endothelial progenitor cells through the HIF-1α/SDF-1 pathway.

The mechanism for the antiangiogenic activity of peroxisome proliferator-activated receptor alpha (PPARα) remains incompletely understood. Endothelial progenitor cells (EPC) are known to participate in neovascularization (NV). The purpose of this study was to investigate whether PPARα regulates EPC during retinal NV. Retinal NV was induced by oxygen-induced retinopathy (OIR). Mice with OIR were injected intraperitoneally with the PPARα agonist fenofibric acid (FA) or with adenovirus expressing PPARα (Ad-PPARα). Flow cytometry was used to quantify circulating and retinal EPC. Serum stromal cell-derived factor 1 (SDF-1) levels were measured by ELISA. Hypoxia was induced in primary human retinal capillary endothelial cells (HRCEC) and mouse brain endothelial cells (MBEC) by CoCl2. Levels of SDF-1 and hypoxia-inducible factor 1 alpha (HIF-1α) were measured by Western blotting. Fenofibric acid and overexpression of PPARα attenuated the increase of circulating and retinal EPC, correlating with suppressed retinal NV in OIR mice at P17. The PPARα knockout enhanced the OIR-induced increase of circulating and retinal EPC. Fenofibric acid decreased retinal HIF-1α and SDF-1 levels as well as serum SDF-1 levels in the OIR model. In HRCEC, PPARα inhibited HIF-1α nuclear translocation and SDF-1 overexpression induced by hypoxia. Further, MBEC from PPARα(-/-) mice showed more prominent activation of HIF-1α and overexpression of SDF-1 induced by hypoxia, compared with the wild-type (WT) MBEC. PPARα failed to block SDF-1 overexpression induced by a constitutively active mutant of HIF-1α, suggesting that regulation of SDF-1 by PPARα was through blockade of HIF-1α activation. Peroxisome proliferator-activated receptor alpha suppresses ischemia-induced EPC mobilization and homing through inhibition of the HIF-1α/SDF-1 pathway. This represents a novel molecular mechanism for PPARα's antiangiogenic effects.

Regulation of human endothelial progenitor cell maturation by polyurethane nanocomposites

The mobilization and homing of endothelial progenitor cells (EPCs) are critical to the development of an antithrombotic cardiovascular prosthesis. Polyurethane (PU) with superior elasticity may provide a mechanical environment resembling that of the natural vascular tissues. The topographical cues of PU were maximized by making nanocomposites with a small amount of gold nanoparticles (AuNPs). The nanocomposites of PU-AuNPs (“PU-Au”) with a favorable response of endothelial cells were previously established. In the current study, the effect of PU and PU-Au nanocomposites on the behavior of human peripheral blood EPCs was investigated in vitro and in vivo. It was found that PU-Au promoted EPCs to become differentiated endothelial cells in vitro, confirmed by the increased expressions of CD31 and VEGF-R2 surface markers. The increased maturation of EPCs was significantly more remarkable on PU-Au, probably through the stromal derived factor 1α (SDF-1α)/CXCR4 signaling pathway. In vivo experiments showed that EPCs seeded on PU-Au coated catheters effectively reduced thrombosis by differentiation into endothelial cells. Surface endothelialization with CD31 and CD34 expression as well as intimal formation with α-SMA expression was significantly accelerated in the group receiving EPC-seeded PU-Au catheters. Moreover, the analysis of collagen deposition revealed a reduction of fibrosis in the group receiving EPC-seeded PU-Au catheters as compared to the other groups. These results suggest that EPCs engineered with a proper elastic substrate may provide unique endothelialization and antithrombogenic properties that benefit vascular tissue regeneration.

MK-0626, A Dipeptidyl Peptidase-4 Inhibitor, Improves Neovascularization by Increasing Both the Number of Circulating Endothelial Progenitor Cells and Endothelial Nitric Oxide Synthetase Expression

Current treatment modalities for critical limb ischemia (CLI) are of limited benefit; therefore, advances in therapeutic vasculogenesis may open an important new avenue for the treatment of CLI. This study examines the therapeutic potential of the DPP-4 inhibitor MK-0626 as a regulator of vasculogenesis in vivo. MK-0626 was administered daily to C57CL/B6 mice and eGFP-labeled bone marrow-transplanted ICR mice that had undergone hind limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neo-vasculogenesis and the number of circulating endothelial progenitor cells (EPCs), respectively. Cell surface markers of EPCs and the level of endothelial nitric oxide synthase (eNOS) were studied in the vessels. Mice that received MK-0626 had an elevated level of glucagon- like peptide-1 (GLP-1) and a decreased level of dipeptidyl peptidase-4 (DPP-4) in their plasma, in addition to an ischemia-induced increase in the level of stromal cell-derived factor-1 (SDF-1). In C57CL/B6 mice, blood flow in the ischemic limb was significantly improved by treatment with MK-0626. The number of circulating EPCs and both the synthesis and phosphorylation of eNOS were also increased in ischemic thigh muscle after MK-0626 treatment. In contrast, similar effects of MK-0626 were not observed in B6.129P2-Nos3(tm1Unc)/J mice (an eNOS knockout mouse). Additionally, MK-0626 treatment promoted the mobilization and homing of EPCs to ischemic tissue in eGFP transgenic mouse bone marrow-transplanted ICR mice. We conclude that both the number of circulating EPCs and neo-vasculogenesis are increased in response to DPP-4 inhibitor treatment and that this occurs via an eNOS-dependent mechanism. The results highlight the therapeutic vasculogenesis potential of the DPP-4 inhibitor MK-0626 using a hind limb ischemia mouse model.

Glycogen Synthase Kinase-3β and Cathepsin B in Diabetic Endothelial Progenitor Cell Dysfunction: An Old Player Finds a New Partner

Microvascular and macrovascular complications associated with type 2 diabetes are leading causes of morbidity and mortality. In fact, cardiovascular (CV) complications account for a major portion of health care costs in patients with diabetes. Although lifestyle changes and pharmacotherapy aimed at CV disease risk factor modification are the mainstay of medical treatment, revascularization (surgical and endovascular) is often necessary to restore tissue perfusion and function. Indeed, nearly 25% of coronary revascularization procedures performed in the U.S. occur in individuals with diabetes (1). Furthermore, diffuse atherosclerosis, impaired ability to form vascular collaterals, and restenosis contribute to higher rates of repeat revascularization in these patients (1). Consequently, cell-based therapy with bone marrow cells and endothelial progenitor cells (EPCs) aimed at inducing angiogenesis and reendothelialization is a promising strategy that is under active investigation in both preclinical and clinical studies (2,3). EPCs constitute a very small subset of circulating blood cells. They are progenitors of endothelial cells and have the ability to proliferate and differentiate to form perfused blood vessels in vivo and tube-like structures in vitro (4). EPC-induced neovascularization in response to tissue hypoxia and injury is a highly coordinated, temporally regulated, and complex set of events that involves mobilization, migration, and homing of EPCs to the target tissue (5,6). Endothelial injury and hypoxia activate the transcription factor hypoxia-induced factor (HIF) to initiate the expression and release of growth factors and chemokines. These include stromal cell–derived factor 1 (SDF-1), vascular endothelial growth factor (VEGF), c-Kit ligand (or SCF), angiopoietin, and interleukin-8 (IL-8), among others (5,6). Platelet aggregation leads to high levels of platelet-derived SDF-1 at the site of endothelial injury (7). EPCs are retained in the bone marrow in distinct niches by their interaction with stromal cells. …

The role of fucosylation in the promotion of endothelial progenitor cells in neovascularization and bone repair

Bone marrow-derived endothelial progenitor cells (EPCs) are being tested as a therapy to treat a variety of ischemic diseases. Poor homing to targeted tissues is one of the major factors limiting the therapeutic efficacy of EPCs. Here, we show that human cord blood-derived EPCs expressed little sialyl Lewis X (sLex) antigen that is necessary for selectin-mediated cell–cell interactions. Expression of α1,3-fucosyltransferase VI (FucT VI) in the EPCs enhanced sLex synthesis, E- and P-selectin-binding, and EPC adhesion to tumor necrosis factor-α-stimulated human umbilical vein endothelial cells in culture. In a mouse model of hind limb ischemia, in which EPCs were injected intravenously, FucT VI expression increased EPC homing, neovascularization, and blood flow in ischemic muscles. In another mouse model of femoral fracture, FucT VI-expressing EPCs were more efficient than control EPCs in targeting to peri-fracture tissues to enhance angiogenesis, blood flow and bone repair. These results indicate that fucosylated EPCs may be used to as an improved cellular source to treat ischemic diseases.

Endothelial progenitor cell homing in human myocardium in patients with coronary artery disease

Endothelialprogenitorcells(EPCs)aremobilizedfrombonemarrowinto peripheral blood, contributing to the revascularization of ischemicareas, to endothelial repair and to the physiological maintenance ofvascularization. EPC mobilization and homing have been primarilylinked to ischemia and inflammation presence [1]. EPCs are directlycorrelated with endothelial function and inversely correlated withcardiovascular risk factors and atherosclerosis progression [2].EPClevelshavealsobeencorrelatedtoprognosisevaluationincardiovascu-lar disease [3].Regarding EPC correlation with coronary artery disease (CAD)presence and severity, an inverse relationship with CAD severity, inde-pendent of traditional risk factors, was demonstrated by EPC colonycounting [4],whileahighnumberofEPCsassociatedwithCADandcorre-latedwithstenosisseveritywereshownby flowcytometry [5].Recentlyanew protocol, adapted from the standardized ISHAGE protocol for hema-topoieticstemcells,hasbeendevelopedforEPClevelevaluationtoenablecomparison of clinical and laboratory data [6].While thepresence of circulatingEPCshasbeenwidely evaluated indifferent diseases, few studies tried to evaluate the presence of EPCs inhuman vital myocardium.TheaimofourstudywastoinvestigateEPClevelsbothinperipheralbloodand inmyocardium in thesame patients atthesame time, evalu-atingthecorrelationwith CADpresence. In bothsampleswequantifiedCD34

MiR-150 enhances the motility of EPCs in vitro and promotes EPCs homing and thrombus resolving in vivo

Deep venous thrombosis (DVT) is one of the common peripheral vascular diseases. The recruitment and migration of bone marrow-derived endothelial progenitor cells (EPCs) to the sites of venous thrombus are necessary in the process of thrombus organization and recanalization. Our objective was to investigate the functional role of miR-150 in rat EPCs and its potential application in deep venous thrombosis. Rat EPCs were cultured and transfected with miR-150 mimics and inhibitor. Wound healing assay, transwell migration assay and matrigel tube formation assay were performed to elucidate the effect of miR-150 of rat EPCs. Lentiviral construct expressing miR-150 was transfected into EPCs and the EPCs were injected to rat models of DVT. The rats were sacrificed on the day of 7 and 14 after the transplantation and the histological study was performed. Luciferase reporter assay and Western blot were performed to evaluate rat miR-150 regulates the expression of c-Myb. MiR-150 significantly promoted the migration and tube formation ability of EPCs in vitro and enhanced EPCs' homing, organization and resolution ability in vivo. Overexpression of miR-150 significantly reduced the protein level of c-Myb and repressed the activity of a luciferase reporter containing both of the two predicted miR-150 binding sites in c-Myb 3'-UTR, indicating that c-Myb may be a miR-150 target gene. MiR-150 enhanced the migration, tube formation, homing, thrombus recanalization and resolution ability of rat EPCs. Restoring miR-150 in EPCs revealed potential application in DVT therapy.

Sustained Release of Engineered Stromal Cell–Derived Factor 1-α From Injectable Hydrogels Effectively Recruits Endothelial Progenitor Cells and Preserves Ventricular Function After Myocardial Infarction

Exogenously delivered chemokines have enabled neovasculogenic myocardial repair in models of ischemic cardiomyopathy; however, these molecules have short half-lives in vivo. In this study, we hypothesized that the sustained delivery of a synthetic analog of stromal cell-derived factor 1-α (engineered stromal cell-derived factor analog [ESA]) induces continuous homing of endothelial progenitor cells and improves left ventricular function in a rat model of myocardial infarction. Our previously designed ESA peptide was synthesized by the addition of a fluorophore tag for tracking. Hyaluronic acid was chemically modified with hydroxyethyl methacrylate to form hydrolytically degradable hydrogels through free-radical-initiated crosslinking. ESA was encapsulated in hyaluronic acid hydrogels during gel formation, and then ESA release, along with gel degradation, was monitored for more than 4 weeks in vitro. Chemotactic properties of the eluted ESA were assessed at multiple time points using rat endothelial progenitor cells in a transwell migration assay. Finally, adult male Wistar rats (n=33) underwent permanent ligation of the left anterior descending (LAD) coronary artery, and 100 µL of saline, hydrogel alone, or hydrogel+25 µg ESA was injected into the borderzone. ESA fluorescence was monitored in animals for more than 4 weeks, after which vasculogenic, geometric, and functional parameters were assessed to determine the therapeutic benefit of each treatment group. ESA release was sustained for 4 weeks in vitro, remained active, and enhanced endothelial progenitor cell chemotaxis. In addition, ESA was detected in the rat heart >3 weeks when delivered within the hydrogels and significantly improved vascularity, ventricular geometry, ejection fraction, cardiac output, and contractility compared with controls. We have developed a hydrogel delivery system that sustains the release of a bioactive endothelial progenitor cell chemokine during a 4-week period that preserves ventricular function in a rat model of myocardial infarction.

Calvarial defect healing by recruitment of autogenous osteogenic stem cells using locally applied simvastatin

Local statins implant has been shown to promote bone healing, the underlying mechanisms are unclear. The purpose of this study was to test the effect of local simvastatin implant on bone defect healing; to evaluate the mobilization, migration, and homing of bone marrow-derived mesenchymal stem cells (BMSCs) and endothelial progenitor cells (EPCs) induced by simvastatin. We found that local simvastatin implant increased bone formation by 51.8% (week 6) and 64.8% (week 12) compared with polyglycolic acid controls (P < 0.01), as verified by X-ray, CT, and histology. Simvastatin increased migration capacity of BMSCs and EPCs in vitro (P < 0.05). Local simvastatin implant increased mobilization of EPCs to the peripheral blood by 127% revealed by FACS analysis (P < 0.01), and increased osteogenic BMSCs to the peripheral blood dramatically revealed by Alizarin Red-S staining for mineralized nodules formation. Pre-transplanted GFP-transfected BMSCs as a tracing cell and bioluminescence imaging revealed that local simvastatin implant recruited GFP-labeled BMSC. Also, local simvastatin implant induced the HIF-1α and BMP-2 expression. In conclusion, local simvastatin implantation promotes bone defect healing, where the underlying mechanism appears to involve the higher expression of HIF-1α and BMP-2, thus recruit autogenous osteogenic and angiogenetic stem cells to the bone defect area implanted with simvastatin.

Tumor necrosis factor-α-activated mesenchymal stem cells promote endothelial progenitor cell homing and angiogenesis

Mesenchymal stem cells (MSCs) accelerate regeneration of ischemic or injured tissues by stimulation of angiogenesis through a paracrine mechanism. Tumor necrosis factor-α (TNF-α)-activated MSCs secrete pro-angiogenic cytokines, including IL-6 and IL-8. In the present study, using an ischemic hindlimb animal model, we explored the role of IL-6 and IL-8 in the paracrine stimulation of angiogenesis and tissue regeneration by TNF-α-activated MSCs. Intramuscular injection of conditioned medium derived from TNF-α-treated MSCs (TNF-α CM) into the ischemic hindlimb resulted in attenuated severe limb loss and stimulated blood perfusion and angiogenesis in the ischemic limb. Immunodepletion of IL-6 and IL-8 resulted in attenuated TNF-α CM-stimulated tissue repair, blood perfusion, and angiogenesis. In addition, TNF-α CM induced migration of human cord blood-derived endothelial progenitor cells (EPCs) through IL-6- and IL-8-dependent mechanisms in vitro. Intramuscular injection of TNF-α CM into the ischemic limb led to augmented homing of tail vein-injected EPCs into the ischemic limb in vivo and immunodepletion of IL-6 or IL-8 from TNF-α CM attenuated TNF-α CM-stimulated homing of EPCs. In addition, intramuscular injection of recombinant IL-6 and IL-8 proteins resulted in increased homing of intravenously transplanted EPCs into the ischemic limb and improved blood perfusion in vivo. These results suggest that TNF-α CM stimulates angiogenesis and tissue repair through an increase in homing of EPCs through paracrine mechanisms involving IL-6 and IL-8.

Increased Circulating Inflammatory Endothelial Cells in Blacks With Essential Hypertension

Morbidity and mortality attributable to hypertension are higher in black essential hypertensive (EH) compared with white EH patients, possibly related to differential effects on vascular injury and repair. Although circulating endothelial progenitor cells (EPCs) preserve endothelial integrity, inflammatory endothelial cells (IECs) detach from sites of injury and represent markers of vascular damage. We hypothesized that blood levels of IECs and inflammatory markers would be higher in black EH compared with white EH patients. Inferior vena cava and renal vein levels of CD34+/KDR+ (EPC) and VAP-1+ (IEC) cells were measured by fluorescence-activated cell sorting in white EH and black EH patients under fixed sodium intake and blockade of the renin–angiotensin system, and compared with systemic levels in normotensive control subjects (n=19 each). Renal vein and inferior vena cava levels of inflammatory cytokines and EPC homing factors were measured by Luminex. Blood pressure, serum creatinine, lipids, and antihypertensive medications did not differ between white and black EH patients, and EPC levels were decreased in both. Circulating IEC levels were elevated in black EH patients, and inversely correlated with EPC levels ( R 2 =0.58; P =0.0001). Systemic levels of inflammatory cytokines and EPC homing factors were higher in black EH compared with white EH patients, and correlated directly with IECs. Renal vein inflammatory cytokines, EPCs, and IECs did not differ from their circulating levels. Most IECs expressed endothelial markers, fewer expressed progenitor cell markers, but none showed lymphocyte or phagocytic cell markers. Thus, increased release of cytokines and IECs in black EH patients may impair EPC reparative capacity and aggravate vascular damage, and accelerate hypertension-related complications.

SAT0051 NF-KAPPAB inducing kinase (NIK) is a key regulator of angiogenesis: Implications for the role of non-canonical NF-KAPPAB signaling in synovial inflammation

BackgroundIn rheumatoid arthritis (RA) synovial tissue (ST), (pathological) angiogenesis can be observed already in the earliest phase of disease, which may be critical in the switch from acute to chronic...

Alcohol Consumption Negates Estrogen-mediated Myocardial Repair in Ovariectomized Mice by Inhibiting Endothelial Progenitor Cell Mobilization and Function

We have shown previously that estrogen (estradiol, E2) supplementation enhances voluntary alcohol consumption in ovariectomized female rodents and that increased alcohol consumption impairs ischemic hind limb vascular repair. However, the effect of E2-induced alcohol consumption on post-infarct myocardial repair and on the phenotypic/functional properties of endothelial progenitor cells (EPCs) is not known. Additionally, the molecular signaling of alcohol-estrogen interactions remains to be elucidated. This study examined the effect of E2-induced increases in ethanol consumption on post-infarct myocardial function/repair. Ovariectomized female mice, implanted with 17β-E2 or placebo pellets were given access to alcohol for 6 weeks and subjected to acute myocardial infarction. Left ventricular functions were consistently depressed in mice consuming ethanol compared with those receiving only E2. Alcohol-consuming mice also displayed significantly increased infarct size and reduced capillary density. Ethanol consumption also reduced E2-induced mobilization and homing of EPCs to injured myocardium compared with the E2-alone group. In vitro, exposure of EPCs to ethanol suppressed E2-induced proliferation, survival, and migration and markedly altered E2-induced estrogen receptor-dependent cell survival signaling and gene expression. Furthermore, ethanol-mediated suppression of EPC biology was endothelial nitric oxide synthase-dependent because endothelial nitric oxide synthase-null mice displayed an exaggerated response to post-acute myocardial infarction left ventricular functions. These data suggest that E2 modulation of alcohol consumption, and the ensuing EPC dysfunction, may negatively compete with the beneficial effects of estrogen on post-infarct myocardial repair.

Irbesartan administration therapeutically influences circulating endothelial progenitor cell and microparticle mobilization by involvement of pro-inflammatory cytokines

Circulating microparticles (MPs) and endothelial progenitor cells (EPCs) correlate with endothelial dysfunction and contribute to the pathogenesis of atherosclerosis. In this context, we explored whether the angiotensin II type I receptor antagonist, irbesartan, exerts a pharmacological control in the atherosclerotic process by the improvement of EPC mobilization and inhibitory effects on MP release and VEGF and SDF-1α levels in the hypertensive–hypercholesterolemic (HH) hamster model. The HH hamsters were treated with irbesartan (50mg/kg b.w/day administered by gavage) for 4 month (HHI). We analyzed MP/EPC infiltration in vascular wall before and after irbesartan administration as well as the endothelial function and expression of VEGF/SDF-1α in plasma and tissue and of molecular pathways activated by them. The results showed that treatment with irbesartan significantly increased EPC infiltration and decreased MP infiltration. The mechanisms underlying this response include the reduction/increase of a number of specific membrane receptors exposed by MPs (TF, P-Selectin, E-Selectin, PSGL-1, Rantes), respectively, by EPCs (β2-Integrins, α4β1-integrin), the augmentation of endothelium-mediated vasodilation and the reduction of protein expression of VEGF/SDF-1α followed by: (1) the diminishment of pro-inflammatory endothelial cytokines: VEGFR1, VEGFR2, CXCR4, Tie2, PIGF with role in EPC homing to sites of damaged endothelium; and (2) the increase of protein expression of COX-2, PGI2 synthase molecules with role in the improvement of arterial wall vasodilatation. In conclusion, the study underlines that irbesartan administration therapeutically improves/reduces EPC, respectively, MP mobilization and this action may be of salutary relevance contributing to its beneficial cardiovascular effects.

Effects of Ischemic Preconditioning in the Late Phase on Homing of Endothelial Progenitor Cells in Renal Ischemia/Reperfusion Injury

ObjectiveThe aim of this study was to determine whether the mobilization and recruitment of endothelial progenitor cells (EPCs) contribute to the protection of kidneys from ischemia/reperfusion (I/R) injury after ischemic preconditioning (IPC) during the late phase. MethodsSeventy-five male Sprague-Dawley rats were divided into the following groups: sham-operated (group A; n = 25), ischemia/reperfusion hosts that underwent 45 minutes of left renal artery ischemia (group B; n = 25), and ischemic preconditioning-treated group (group C; n = 25). Group C underwent 3 cycles of 5 minutes of occlusion and 5 minutes of reperfusion followed by 24 hours of reperfusion before the following 45 minutes of occlusion. Serum samples were collected and renal tissues harvested for histological examination terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, immunohistochemical staining, and Western blot analysis to determine the expression levels of CD34, VEGFR-2 (Vascular Endothelial Growth Factor Receptor 2)/flk-1, vascular endothelial growth factor (VEGF), and stromal cell–derived factor-1α (SDF-1α). ResultsCompared with group B, the levels of blood urea nitrogen (BUN), serum creatinine (Scr) and acute tubulointerstitial injury at 24 hours after operation were significantly reduced in group C. At 72 hours, tubular epithelial cell apoptosis was also decreased (17.6 ± 4.45 vs 63.8 ± 6.10; P < .01). CD34+ and flk-1+ cells that mostly accumulated in the medullopapillary parenchyma were significantly increased at 72 hours (P < .05). Expression levels of VEGF and SDF-1α were also significantly higher in group C (P < .05). ConclusionThe present work suggested that IPC protected kidneys from IR injury in the later phase through enhanced mobilization and recruitment of EPCs. VEGF and SDF-1α may play important roles in this protective effect.

The Injury Theory, Endothelial Progenitors, and Sleep Apnea

The Injury Theory, Endothelial Progenitors, and Sleep Apnea

Bone Marrow Rejuvenation

Aging has been defined as “the sum of primary restrictions in regenerative mechanisms of multicellular organisms”.1 In other words, aging can also be described as a progressive functional decline; a gradual degeneration of physiological function; or the intrinsic, inevitable and irreversible time-related process of loss of viability and increase in disease vulnerability.2 As life expectancy rises, it has led to the rapid aging of populations. Aging is the key risk factor for major human chronic pathologies and has become a worldwide medical and social problem. The most common diseases of aging include Alzheimer's, arthritis, cancer, diabetes, depression and cardiovascular disorders. Certainly, increasing age is also an independent risk factor for the development of atherosclerosis and coronary artery disease.3, 4 Aging is accompanied by endothelial cell senescence and the progressive decline of endothelial function.5 Endothelial dysfunction primarily contributes to impeded re-endothelialization and exacerbated neointima formation upon vascular pathological lesions. Thus, recovery from the decline of endothelial function helps to prevent age-related vascular disease. With increasing age and persistent reactive oxygen species production, the capacity of adjacent endothelial cells to repair endothelial injuries is limited, and vascular recovery becomes dependent on the incorporation of circulating endothelial progenitor cells (EPCs).6 Bone marrow-derived circulating EPCs play a significant role in vascular re-endothelialization and suppression of neointima formation after vascular injury.7 These cells can be mobilized under the modulation of vascular endothelial growth factor (VEGF), matrix metallopeptidase-9 (MMP-9) and other factors to participate in repair of endothelial injury. Aging impairs EPC mobilization, migration and homing to sites of vascular injury (Fig. 1). Open in a separate window Figure 1 Age-related effects that impair the biological function of endothelial progenitor cells.

Androgens Modulate Endothelial Function and Endothelial Progenitor Cells in Erectile Physiology

The incidence of erectile dysfunction (ED) increases with age and cardiovascular disease risk factors, such as hypertension, hyperlipidemia, insulin resistance, obesity, and diabetes. These risk factors are thought to contribute to endothelial dysfunction and atherosclerosis, thus contributing to the pathophysiology of ED. The role of the endothelium in regulating erectile physiology is well established. However, the role of androgens in modulating endothelial function and endothelial repair mechanisms subsequent to vascular injury in erectile tissue remains a subject of intensive research. The clinical and preclinical evidence discussed in this review suggests that androgens regulate endothelial function and also play an important role in the development and maturation of endothelial progenitor cells (EPCs), which are thought to play a critical role in repair of endothelial injury in vascular beds. In this review, we discuss the data available on the effects of androgens on endothelial function and EPCs in the repair of vascular injury. Indeed, more research is needed to fully understand the molecular and cellular basis of androgen action in regulating the development, differentiation, maturation, migration, and homing of EPCs to the site of injury. A better understanding of these processes will be critical to the development of new therapeutic approaches to the treatment of vascular ED.