Circulating endothelial progenitor cells do not contribute to regeneration of endothelium after murine arterial injury

Hagensen, Mette K.; Raarup, Merete K.; Mortensen, Martin Bødtker; Thim, Troels; Nyengaard, Jens Randel; Falk, Erling; Bentzon, Jacob F.

doi:10.1093/cvr/cvr278

Cited by 86 publications

(71 citation statements)

References 38 publications

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“…22 However, recent evidence challenged the presumed involvement of endothelial progenitor cells in endothelial restoration. Hagensen et al 3,23 demonstrated that circulating endothelial progenitor cells did neither contribute to the maintenance and regeneration of plaque endothelium in atherosclerotic mice nor to endothelial regeneration after wire-induced vascular injury. In our study, we found accelerated reendothelialization after systemic EMP treatment without any changes in circulating sca1/flk1 positive cell levels, suggesting effects of EMPs predominantly on mature ECs.…”

Section: Discussionmentioning

confidence: 99%

Endothelial Microparticle–Mediated Transfer of MicroRNA-126 Promotes Vascular Endothelial Cell Repair via SPRED1 and Is Abrogated in Glucose-Damaged Endothelial Microparticles

et al. 2013

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Background-Repair of the endothelium after vascular injury is crucial for preserving endothelial integrity and preventing the development of vascular disease. The underlying mechanisms of endothelial cell repair are largely unknown. We sought to investigate whether endothelial microparticles (EMPs), released from apoptotic endothelial cells (ECs), influence EC repair. Methods and Results-Systemic treatment of mice with EMPs after electric denudation of the endothelium accelerated reendothelialization in vivo. In vitro experiments revealed that EMP uptake in ECs promotes EC migration and proliferation, both critical steps in endothelial repair. To dissect the underlying mechanisms, Taqman microRNA array was performed, and microRNA (miR)-126 was identified as the predominantly expressed miR in EMPs. The following experiments demonstrated that miR-126 was transported into recipient human coronary artery endothelial cells by EMPs and functionally regulated the target protein sprouty-related, EVH1 domain-containing protein 1 (SPRED1). Knockdown of miR-126 in EMPs abrogated EMP-mediated effects on human coronary artery endothelial cell migration and proliferation in vitro and reendothelialization in vivo. Interestingly, after simulating diabetic conditions, EMPs derived from glucose-treated ECs contained significantly lower amounts of miR-126 and showed reduced endothelial repair capacity in vitro and in vivo. Finally, expression analysis of miR-126 in circulating microparticles from 176 patients with stable coronary artery disease with and without diabetes mellitus revealed a significantly reduced miR-126 expression in circulating microparticles from diabetic patients. Conclusions-Endothelial

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Section: Discussionmentioning

confidence: 99%

Endothelial Microparticle–Mediated Transfer of MicroRNA-126 Promotes Vascular Endothelial Cell Repair via SPRED1 and Is Abrogated in Glucose-Damaged Endothelial Microparticles

et al. 2013

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“…33 Although some commentators have drawn into question the contribution of progenitor cells to normal vascular homeostasis, 34,35 our demonstration here that infusion of cells enhances regeneration adds to the evidence that such cells offer therapeutic potential. Bone marrow cells enriched for the stem cell marker CD117 (c-kit) represent a promising population to augment vascular repair, and we have previously shown these cells to accelerate endothelial regeneration in the context of insulin resistance.…”

Section: Discussionmentioning

confidence: 68%

Haploinsufficiency of the Insulin-Like Growth Factor-1 Receptor Enhances Endothelial Repair and Favorably Modifies Angiogenic Progenitor Cell Phenotype

Yuldasheva

Rashid

Haywood

et al. 2014

ATVB

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Objectives— Defective endothelial regeneration predisposes to adverse arterial remodeling and is thought to contribute to cardiovascular disease in type 2 diabetes mellitus. We recently demonstrated that the type 1 insulin-like growth factor receptor (IGF1R) is a negative regulator of insulin sensitivity and nitric oxide bioavailability. In this report, we examined partial deletion of the IGF1R as a potential strategy to enhance endothelial repair. Approach and Results— We assessed endothelial regeneration after wire injury in mice and abundance and function of angiogenic progenitor cells in mice with haploinsufficiency of the IGF1R (IGF1R +/− ). Endothelial regeneration after arterial injury was accelerated in IGF1R +/− mice. Although the yield of angiogenic progenitor cells was lower in IGF1R +/− mice, these angiogenic progenitor cells displayed enhanced adhesion, increased secretion of insulin-like growth factor-1, and enhanced angiogenic capacity. To examine the relevance of IGF1R manipulation to cell-based therapy, we transfused IGF1R +/− bone marrow–derived CD117 + cells into wild-type mice. IGF1R +/− cells accelerated endothelial regeneration after arterial injury compared with wild-type cells and did not alter atherosclerotic lesion formation. Conclusions— Haploinsufficiency of the IGF1R is associated with accelerated endothelial regeneration in vivo and enhanced tube forming and adhesive potential of angiogenic progenitor cells in vitro. Partial deletion of IGF1R in transfused bone marrow–derived CD117 + cells enhanced their capacity to promote endothelial regeneration without altering atherosclerosis. Our data suggest that manipulation of the IGF1R could be exploited as novel therapeutic approach to enhance repair of the arterial wall after injury.

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“…The pathological progress of coiled cerebral aneurysms has been shown to be affected by the interaction of many factors, including EPCs, smooth muscle cells, and inflammation. Although bone marrow-derived EPCs were shown not to be involved in the re-endothelialization of a mouse endothelial denudation model or murine arterial injury model, 13 EPCs were thought to play a key role in the regulation of postinjury vascular endothelialization by secreting cytokines or microvesicles containing DNA, RNA, or microRNA. 6,26 The beneficial effects of statins in clinical aneurysm treatment are also controversial.…”

Section: Discussionmentioning

confidence: 99%

Rosuvastatin for enhancement of aneurysm neck endothelialization after coil embolization: promotion of endothelial progenitor cells in a rodent model

Liu

Chen

et al. 2016

JNS

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OBJECT Coil embolization is a safe, efficient, and minimally invasive technique for the treatment of intracranial aneurysms. However, coil embolization is associated with a higher risk of recurrence than clip ligation. In this study, the authors explore a new approach through the promotion of endothelial progenitor cells (EPCs) to optimize endothelialization of the aneurysm neck and reduce the risk of recurrence. METHODS A coiled aneurysm model was created in 48 adult male Sprague-Dawley rats via microsurgery. Half of these animals were treated with rosuvastatin (20 mg/kg) in saline via gavage for 10, 20, or 30 days. The other half were administered saline without rosuvastatin. An additional 15 rats underwent “mock surgery” (identical anesthesia and saline gavage but no surgery). The endothelial repair process in the coiled aneurysms was evaluated via flow cytometry, im-munostaining, and electronic microscopy. The mock surgery group was used for comparison in flow cytometry studies. The effects of rosuvastatin on viability and functioning of Sprague-Dawley rat bone marrow-derived EPCs were also explored via MTT, migration, and tube formation assays. RESULTS The aneurysm neck repair score was significantly higher in the rosuvastatin-treated rats than in the untreated rats (p < 0.05). The circulating EPC count was increased and maintained at a higher level in rosuvastatin-treated rats compared with the aneurysm rats that did not receive rosuvastatin (p < 0.05). Immunostaining showed that the aneurysm neck endothelium was more integrated and the number of kinase insert domain receptor-positive cells was increased in the rosuvastatin-treated rats. Further study demonstrated that rosuvastatin promoted EPC proliferation, migration, and tube formation. CONCLUSIONS Rosuvastatin promoted endothelialization of the coiled aneurysm neck via induction of EPCs, suggesting that promoting endothelialization provides an additional therapeutic opportunity during vascular endothelium repair.

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Circulating endothelial progenitor cells do not contribute to regeneration of endothelium after murine arterial injury

Abstract: Endothelial regeneration after vascular injury did not involve circulating EPCs but was mediated solely by migration of ECs from the adjacent healthy endothelium.

Cited by 86 publications

References 38 publications

Endothelial Microparticle–Mediated Transfer of MicroRNA-126 Promotes Vascular Endothelial Cell Repair via SPRED1 and Is Abrogated in Glucose-Damaged Endothelial Microparticles

Endothelial Microparticle–Mediated Transfer of MicroRNA-126 Promotes Vascular Endothelial Cell Repair via SPRED1 and Is Abrogated in Glucose-Damaged Endothelial Microparticles

Haploinsufficiency of the Insulin-Like Growth Factor-1 Receptor Enhances Endothelial Repair and Favorably Modifies Angiogenic Progenitor Cell Phenotype

Rosuvastatin for enhancement of aneurysm neck endothelialization after coil embolization: promotion of endothelial progenitor cells in a rodent model

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