Endothelial Progenitor Cells Contribute to the Vascularization of Endometriotic Lesions

Laschke, Matthias W.; Giebels, Christian; Nickels, Ruth M.; Scheuer, Cláudia; Menger, Michael D.

doi:10.1016/j.ajpath.2010.11.037

Cited by 61 publications

(51 citation statements)

References 31 publications

(29 reference statements)

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“…Besides angiogenesis, vascularization of endometriotic lesions also involves vasculogenesis, which is defined as de novo formation of microvessels from circulating endothelial progenitor cells [41][42][43]. Although not further analyzed in the present study, the suppression of this process may have been an additional mechanism contributing to the reduced functional capillary density of endometriotic lesions in quinalizarin-treated animals.…”

Section: Discussionmentioning

confidence: 64%

Protein kinase CK2 is a regulator of angiogenesis in endometriotic lesions

et al. 2012

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Endometriosis is a frequent gynecological disease, which is crucially dependent on the process of angiogenesis. However, the underlying regulatory mechanisms of blood vessel development are still poorly understood. CK2 is a pleiotropic protein kinase, which is implicated in the regulation of various cellular processes including angiogenesis. Herein we studied for the first time the function of protein kinase CK2 in angiogenesis of endometriotic lesions. For this purpose, we analyzed the anti-angiogenic activity of the CK2 inhibitor quinalizarin in a rat aortic ring assay and its effect on the expression of individual CK2 subunits and on kinase activity in endometrial tissue. Moreover, endometriotic lesions were induced in dorsal skinfold chambers of quinalizarin- and vehicle-treated C57BL/6 mice to study their vascularization and morphology by means of repetitive intravital fluorescence microscopy and histology. Our results demonstrate that quinalizarin dose-dependently inhibits vascular sprouting. In addition, treatment of endometrial tissue with quinalizarin reduces CK2 activity without affecting the expression of the three CK2 subunits α, α' and β. In the dorsal skinfold chamber model of endometriosis, quinalizarin inhibits the vascularization of endometriotic lesions, which exhibit a significantly decreased vascularized area and functional capillary density when compared to those of vehicle-treated controls. This is associated with a reduced lesion size and histological fraction of endometrial glands. These findings indicate that CK2 is a regulator of angiogenesis in endometriotic lesions. Accordingly, inhibition of CK2 represents a novel option in the development of anti-angiogenic strategies for the treatment of endometriosis.

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Section: Discussionmentioning

confidence: 64%

Protein kinase CK2 is a regulator of angiogenesis in endometriotic lesions

et al. 2012

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“…15 In this model, the bone marrow of FVB/N wild-type mice is replaced by bone marrow from FVB/N-TgN (Tie2/GFP) 287 Sato mice. For this purpose, the mice are lethally irradiated, which affects the physiological function of the ovary.…”

Section: Discussionmentioning

confidence: 99%

“…6,7,28 Recent reports provide evidence that the vascularization of endometriotic lesions is not only driven by angiogenesis but also involves vasculogenesis. 14,15 The latter mechanism of blood vessel development is characterized by homing of circulating EPCs to the lesions, where they are incorporated into the Detailed information about the individual genes is provided in GenBank (http://www.ncbi.nlm.nih.gov/genbank) using the provided accession numbers. RT-qPCR, quantitative RT-PCR.…”

Section: Discussionmentioning

confidence: 99%

“…13 Besides, we and others have recently demonstrated that the vascularization of endometriotic lesions also involves vasculogenesis [ie, the de novo formation of blood vessels from circulating bone marrowederived endothelial progenitor cells (EPCs), which home to the lesions and are incorporated into the microvascular endothelium]. 14,15 This observation not only adds a novel biological process to the complex pathophysiology of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 endometriosis, but also offers the possibility to develop novel EPC-based approaches for the future diagnosis and therapy of the disease. A major prerequisite to achieve this goal is the detailed knowledge of the mechanisms that regulate vasculogenesis in endometriosis.…”

Section: Q4mentioning

confidence: 99%

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Estrogen Stimulates Homing of Endothelial Progenitor Cells to Endometriotic Lesions

Rudzitis‐Auth

Nenicu

Nickels

et al. 2016

The American Journal of Pathology

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The incorporation of endothelial progenitor cells (EPCs) into microvessels contributes to the vascularization of endometriotic lesions. Herein, we analyzed whether this vasculogenic process is regulated by estrogen. Estrogen- and vehicle-treated human EPCs were analyzed for migration and tube formation. Endometriotic lesions were induced in irradiated FVB/N mice, which were reconstituted with bone marrow from FVB/N-TgN (Tie2/green fluorescent protein) 287 Sato mice. The animals were treated with 100 μg/kg β-estradiol 17-valerate or vehicle (control) over 7 and 28 days. Lesion growth, cyst formation, homing of green fluorescent protein(+)/Tie2(+) EPCs, vascularization, cell proliferation, and apoptosis were analyzed by high-resolution ultrasonography, caliper measurements, histology, and immunohistochemistry. Numbers of blood circulating EPCs were assessed by flow cytometry. In vitro, estrogen-treated EPCs exhibited a higher migratory and tube-forming capacity when compared with controls. In vivo, numbers of circulating EPCs were not affected by estrogen. However, estrogen significantly increased the number of EPCs incorporated into the lesions' microvasculature, resulting in an improved early vascularization. Estrogen further stimulated the growth of lesions, which exhibited massively dilated glands with a flattened layer of stroma. This was mainly because of an increased glandular secretory activity, whereas cell proliferation and apoptosis were not markedly affected. These findings indicate that vasculogenesis in endometriotic lesions is dependent on estrogen, which adds a novel hormonally regulated mechanism to the complex pathophysiology of endometriosis.

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“…When TEMs are specifically depleted, endothelial cells fail to organize effectively in neovessels and undergo programmed cell death, leading to disruption of the lesions. The preferential localization of TEM in perivascular areas 16 and their relative proximity to endothelial cells may provide survival and growth signals to endothelial cells, and possibly also to endothelial progenitor cells 55 Indeed, recent gene profiling studies of tumor-derived TEMs and other TAM subsets showed that TEMs express several proangiogenic and survival factors, including insulin-like growth factor 1. 20 Previous studies have indicated that macrophage alternative activation is critical for endometriosis.…”

Section: Discussionmentioning

confidence: 99%