Number and Migratory Activity of Circulating Endothelial Progenitor Cells Inversely Correlate With Risk Factors for Coronary Artery Disease

Vasa, Mariuca; Fichtlscherer, Stephan; Aicher, Alexandra; Adler, Klaudia; Urbich, Carmen; Martin, Hans; Zeiher, Andreas M.; Dimmeler, Stefanie

doi:10.1161/hh1301.093953

Cited by 2,138 publications

(1,969 citation statements)

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“…Numerous studies have reported inverse correlations of EPC numbers and migratory function with low‐density lipoprotein cholesterol 15, 19. The data we present in this study are the first to demonstrate a cell autonomous role for LXRs in the cholesterol‐mediated dysfunction of EPCs.…”

Section: Discussionsupporting

confidence: 62%

“…These changes in EPC differentiation and secretome were recapitulated when Lxr αβ −/− chow EPCs (but not WT chow EPCs) were treated with cholesterol in culture, suggesting that this was the component of the WD mediating this change. Interestingly, previous clinical studies of EPCs from patients with cardiovascular disease or diabetes mellitus provide evidence that EPCs may passively contribute to disease progression by reducing the migration, proliferation, or tube formation capacity of the cells 15, 18. However, herein we show that the loss of LXRs combined with an increase in EPC cholesterol content produces an EPC population that may actively contribute to disease progression by directly promoting monocyte adhesion to activated endothelial cells.…”

Section: Discussioncontrasting

confidence: 41%

“…In vivo, circulating EPC numbers and the function of EPCs are decreased in patients with cardiovascular disease or diabetes mellitus 15, 16, 17, 18. Reports have demonstrated inverse correlations between EPC numbers/function and low‐density lipoprotein cholesterol levels,15, 19 suggesting a potential role for cholesterol in the dysfunction of EPCs. To date, only a few studies have investigated the specific role of BM‐derived EPCs in the in vivo resolution of atherosclerosis using mouse models 20, 21, 22, 23, 24, 25, 26.…”

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confidence: 99%

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Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells

Rasheed

Tsai

Cummins

2018

JAHA

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BackgroundThe liver X receptors (LXRs; α/β) are nuclear receptors known to regulate cholesterol homeostasis and the production of select hematopoietic populations. The objective of this study was to determine the importance of LXRs and a high‐fat high‐cholesterol diet on global hematopoiesis, with special emphasis on endothelial progenitor cells (EPCs), a vasoreparative cell type that is derived from bone marrow hematopoietic stem cells.Methods and ResultsWild‐type and LXR double‐knockout (Lxrαβ−/−) mice were fed a Western diet (WD) to increase plasma cholesterol levels. In WD‐fed Lxrαβ−/− mice, flow cytometry and complete blood cell counts revealed that hematopoietic stem cells, a myeloid progenitor, and mature circulating myeloid cells were increased; EPC numbers were significantly decreased. Hematopoietic stem cells from WD‐fed Lxrαβ−/− mice showed increased cholesterol content, along with increased myeloid colony formation compared with chow‐fed mice. In contrast, EPCs from WD‐fed Lxrαβ−/− mice also demonstrated increased cellular cholesterol content that was associated with greater expression of the endothelial lineage markers Cd144 and Vegfr2, suggesting accelerated differentiation of the EPCs. Treatment of human umbilical vein endothelial cells with conditioned medium collected from these EPCs increased THP‐1 monocyte adhesion. Increased monocyte adhesion to conditioned medium–treated endothelial cells was recapitulated with conditioned medium from Lxrαβ−/− EPCs treated with cholesterol ex vivo, suggesting cholesterol is the main component of the WD inducing EPC dysfunction.Conclusions LXRs are crucial for maintaining the balance of hematopoietic cells in a hypercholesterolemic environment and for mitigating the negative effects of cholesterol on EPC differentiation/secretome changes that promote monocyte‐endothelial adhesion.

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Section: Discussionsupporting

confidence: 62%

Section: Discussioncontrasting

confidence: 41%

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confidence: 99%

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Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells

Rasheed

Tsai

Cummins

2018

JAHA

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“…The correlations noted are likely the result of previously reported relationships between endothelial function and EPC numbers, and function 35,36 along with the relationship between endothelial number and FMD. 37 All of these are altered in hypertension, 3,38,39 and in these alterations oxidative stress has a pivotal role. 40 Relationships between EPCs, FMD and HO-1 LA Calò et al in BS/GS patients.…”

Section: Discussionmentioning

confidence: 99%

Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin II signaling

et al. 2011

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Angiotensin II (Ang II) is essential for endothelial progenitor cells (EPCs) function as Ang-II-induced oxidative stress causes senescence of EPCs and endothelial dysfunction and Ang II type 1 receptor blockers increase EPCs. Moreover, EPCs activity is dependent on nitric oxide (NO) and heme oxygenase (HO)-1 as these correlate with EPCs senescence and are reduced in hypertensives. Bartter's/Gitelman's syndrome patients (BS/GS), have increased Ang II yet normo/hypotension along with blunted Ang II signaling, reduced oxidative stress, increased NO and HO-1, thus presenting a unique system to explore EPC biology and its relationship with vascular clinical and biochemical correlates. Circulating EPCs, NO-dependent vasodilation (flow-mediated dilation (FMD)) and HO-1 gene expression were characterized in 10 BS/GS patients and in 10 normotensive subjects. EPCs defined by cell surface antigens CD34+kinase-insert domain receptor (KDR+), CD133+KDR+ and CD133+CD34+KDR+ cells were quantitiated via direct three-color flow-cytometry analysis, HO-1 gene expression by reverse transcription-PCR and FMD by B-mode echo scan of the right brachial artery. Correlation analysis was carried out regarding FMD and EPCs, FMD and HO-1 and EPCs and HO-1. In BS/GS, CD34+KDR+ cell numbers did not differ from controls while CD133+KDR+ and CD133+CD34+ KDR+ cell numbers were higher. HO-1 gene expression, as well as FMD, was higher in BS/GS compared with controls. Both CD133+KDR+ and CD133+CD34+KDR+ strongly correlated with both FMD and HO-1. FMD and HO-1 were also strongly correlated. These results document in a human system that EPC numbers and specific populations are related to important clinical and biochemical factors involved in cardiovascular (CV) status and reaffirm the utility of BS/GS patients as a useful system to investigate EPC's role(s) in the pathophysiology of cardiovascular remodeling in humans.

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“…One of the major concerns when envisioning autologous (progenitor/stem) cell therapy in cardiovascular medicine, is the presumed dysfunctional progenitor cell phenotype in older and diseased patients burdened with risk factors, as evidenced for early outgrowth EPCs of monocytic origin (also known as circulating angiogenic cells),9, 10, 11, 12 CD133 + /VEGFR2+ circulating EPCs,10, 13 colony‐forming‐unit EPCs (CFU‐Hill),13, 14 bone‐marrow–derived mononuclear cells (MNCs)15 and hematopoietic stem cells 11…”

Section: Introductionmentioning

confidence: 99%

Neovascularization Potential of Blood Outgrowth Endothelial Cells From Patients With Stable Ischemic Heart Failure Is Preserved

Dauwe

Pelacho

Wibowo

et al. 2016

JAHA

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BackgroundBlood outgrowth endothelial cells (BOECs) mediate therapeutic neovascularization in experimental models, but outgrowth characteristics and functionality of BOECs from patients with ischemic cardiomyopathy (ICMP) are unknown. We compared outgrowth efficiency and in vitro and in vivo functionality of BOECs derived from ICMP with BOECs from age‐matched (ACON) and healthy young (CON) controls.Methods and ResultsWe isolated 3.6±0.6 BOEC colonies/100×106 mononuclear cells (MNCs) from 60‐mL blood samples of ICMP patients (n=45; age: 66±1 years; LVEF: 31±2%) versus 3.5±0.9 colonies/100×106 MNCs in ACON (n=32; age: 60±1 years) and 2.6±0.4 colonies/100×106 MNCs in CON (n=55; age: 34±1 years), P=0.29. Endothelial lineage (VEGFR2+/CD31+/CD146+) and progenitor (CD34+/CD133−) marker expression was comparable in ICMP and CON. Growth kinetics were similar between groups (P=0.38) and not affected by left ventricular systolic dysfunction, maladaptive remodeling, or presence of cardiovascular risk factors in ICMP patients. In vitro neovascularization potential, assessed by network remodeling on Matrigel and three‐dimensional spheroid sprouting, did not differ in ICMP from (A)CON. Secretome analysis showed a marked proangiogenic profile, with highest release of angiopoietin‐2 (1.4±0.3×105 pg/106 ICMP‐BOECs) and placental growth factor (5.8±1.5×103 pg/106 ICMP BOECs), independent of age or ischemic disease. Senescence‐associated β‐galactosidase staining showed comparable senescence in BOECs from ICMP (5.8±2.1%; n=17), ACON (3.9±1.1%; n=7), and CON (9.0±2.8%; n=13), P=0.19. High‐resolution microcomputed tomography analysis in the ischemic hindlimb of nude mice confirmed increased arteriogenesis in the thigh region after intramuscular injections of BOECs from ICMP (P=0.025; n=8) and CON (P=0.048; n=5) over vehicle control (n=8), both to a similar extent (P=0.831).Conclusions BOECs can be successfully culture‐expanded from patients with ICMP. In contrast to impaired functionality of ICMP‐derived bone marrow MNCs, BOECs retain a robust proangiogenic profile, both in vitro and in vivo, with therapeutic potential for targeting ischemic disease.

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Number and Migratory Activity of Circulating Endothelial Progenitor Cells Inversely Correlate With Risk Factors for Coronary Artery Disease

Abstract: Abstract-Recent studies provide increasing evidence that postnatal neovascularization involves bone marrow-derived circulating endothelial progenitor cells (EPCs).

Cited by 2,138 publications

References 49 publications

Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells

Loss of the Liver X Receptors Disrupts the Balance of Hematopoietic Populations, With Detrimental Effects on Endothelial Progenitor Cells

Endothelial progenitor cells relationships with clinical and biochemical factors in a human model of blunted angiotensin II signaling

Neovascularization Potential of Blood Outgrowth Endothelial Cells From Patients With Stable Ischemic Heart Failure Is Preserved

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