<i>Egfl7</i>, a novel epidermal growth factor‐domain gene expressed in endothelial cells

Fitch, Michael J.; Campagnolo, Luisa; Stuhlmann, Heidi

doi:10.1002/dvdy.20063

Cited by 152 publications

(212 citation statements)

References 41 publications

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“…In this paper, we provide proof-of-concept of such a relationship between intronic miR-126* and its host gene, 'epidermal growth factorlike domain 7 or Egfl7 (NP_057299). Also known as VE-statin (vascular endothelial statin) or Neu1, Egfl7 is the first identified inhibitor of mural cell (vascular smooth muscle cells and pericytes) migration, specifically produced by endothelial cells [24][25][26][27]. We show that prostate cells are naturally deficient in miR-126*, supporting recent miRNA tissue profiling [28] and that this is due to poor Egfl7 gene expression.…”

Section: Introductionsupporting

confidence: 72%

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Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells

2008

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MicroRNAs (miRNAs) are endogenous noncoding RNAs that down-regulate gene expression by promoting cleavage or translational arrest of target mRNAs. While most miRNAs are transcribed from their own dedicated genes, some map to introns of 'host' transcripts, the biological significance of which remains unknown. Here, we show that prostate cells are naturally devoid of EGF-like domain 7 (Egfl7) transcripts and hence also deficient in a miRNA, miR-126*, generated from splicing and processing of its ninth intron. Use of recombinant and synthetic miRNAs or a specific antagomir established a role of miR-126* in silencing prostein in non-endothelial cells. We mapped two miR-126*-binding sites in the 3′UTR of the prostein mRNA required for translational repression. Transfection of synthetic miR-126* into prostate cancer LNCaP cells strongly reduced the translation of prostein. Interestingly, loss of prostein correlated with reduction of LNCaP cell migration and invasion. Thus, the robust expression of prostein protein in the prostate cells results from a combination of transcriptional activation of the prostein gene and absence of intronic miRNA-126* due to the prostate-specific repression of the Egfl7 gene. We conclude that intronic miRNAs from tissue-specific transcripts, or their natural absence, make cardinal contributions to cellular gene expression and phenotype. These findings also open the door to tissue-specific miRNA therapy.

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Section: Introductionsupporting

confidence: 72%

“…Egfl7 is expressed at high levels in the vasculature associated with tissue proliferation and is abundant in such organs as heart, lung, ovary, and uterus [24][25][26][27]. In the developing embryo, it is expressed very early during endothelial differentiation and later in all embryonic blood vessels.…”

Section: Discussionmentioning

confidence: 99%

Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells

2008

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“…15 Egfl7 encodes a secreted protein with an apparent molecular weight of ϳ41 kd that contains an aminoterminal signal peptide and two centrally located EGF domains. Expression of Egfl7 during embryonic development is restricted to vascular endothelial cells and their precursors in the blood islands of the visceral yolk sac, largely overlapping with that of PECAM-1/CD31.…”

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confidence: 99%

“…Expression of Egfl7 during embryonic development is restricted to vascular endothelial cells and their precursors in the blood islands of the visceral yolk sac, largely overlapping with that of PECAM-1/CD31. 15 Egfl7 (also named VE-statin, Zneu1, and Notch4-like) has been independently isolated by others. 16,17 In a first approach to understanding the biological role of Egfl7 in adults, we studied the expression of Egfl7 in the normal adult vasculature, during angiogenesis in the pregnant uterus, and in models of arterial injury.…”

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confidence: 99%

EGFL7 Is a Chemoattractant for Endothelial Cells and Is Up-Regulated in Angiogenesis and Arterial Injury

Campagnolo¹,

Leahy²,

Chitnis³

et al. 2005

The American Journal of Pathology

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The endothelium of the adult vasculature is normally quiescent, with the exception of the vasculature of the female reproductive system. However, in response to appropriate stimuli (ie, wound healing, atherosclerosis, tumor growth and metastasis, arthritis) the vasculature becomes activated and grows new capillaries through angiogenesis. We have recently identified a novel endothelial-restricted gene, Egfl7, that encodes a 41-kd secreted protein (Fitch MJ, Campagnolo L, Kuhnert F, Stuhlmann H: Egfl7, a novel epidermal growth factor-domain gene expressed in endothelial cells. Dev Dyn 2004, 230:316 -324). Egfl7 is expressed at high levels early during mouse embryonic development and is strictly associated with the vascular bed. In this study, we investigated Egfl7 expression in the quiescent adult vasculature, in the pregnant uterus, and in two different models of arterial injury, namely ballooning and ferric chloride injury. By RNA in situ hybridization, Egfl7 expression in the vasculature was found to be restricted to the endothelium of the capillaries and mature vessels. In the pregnant uterus, increased vascularization was accompanied by up-regulation of Egfl7. On arterial injury, Egfl7 expression was up-regulated in the regenerating endothelium, but not in the neointima. Importantly, the EGFL7 protein acted as a chemoattractant for embryonic endothelial cells and fibroblasts in a cell migration assay. Together, these results suggest that Egfl7 functions in the formation and maintenance of endothelial integrity and that its up- In the adult mammalian organism, the vasculature is normally quiescent. Arterial endothelial cells have an extremely low turnover rate (ϳ1 in every 10 5 cells undergoes cell division 1 ). However, adult endothelial cells are not postmitotic and, in response to appropriate stimuli, they can proliferate and form new blood vessels by a process termed angiogenesis. 2-4 Angiogenesis describes the formation of new capillaries and larger vessels by sprouting or splitting from pre-existing vessels. Typically, the sprouting of vessels involves activation of quiescent endothelial cells, proteolytic degradation of the extracellular matrix, chemotactic migration, invasion into the surrounding stroma, proliferation and differentiation of endothelial cells, and formation of a new lumen and maturation of the endothelium. 2,[5][6][7][8] This angiogenic sprouting process occurs under physiological conditions during the female reproductive cycle (ovulation, implantation, pregnancy) and wound healing, as well as under pathological conditions in solid tumors and metastases, rheumatoid arthritis, retinopathies, hemangiomas, and psoriasis. 2,7,9,10 Several of the key players in both embryonic and adult angiogenesis are vascular-specific growth factor ligands

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“…One of the key factors that play a role in the regulation of vascular development is EGFL7 (also called VEstatin; Soncin et al, 2003), a secreted protein with an evolutionarily conserved structure and expression pat-tern from fish to human (Fitch et al, 2004;Parker et al, 2004). Egfl7 is expressed exclusively in ECs and their progenitors.…”

Section: Introductionmentioning

confidence: 99%

Egfl7 knockdown causes defects in the extension and junctional arrangements of endothelial cells during zebrafish vasculogenesis

Mazière

Parker²,

Dijk

et al. 2008

Developmental Dynamics

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The endothelial cell (EC) -specific secreted protein EGFL7 is important for tubulogenesis in newly forming blood vessels. We studied its role in vascular tube formation by a quantitative ultrastructural analysis of Egfl7-knockdown zebrafish embryos. At 24 hours postfertilization, the endothelia of dorsal aorta (DA) and posterior cardinal vein (PCV) were correctly anchored to the hypochord and endoderm, respectively, but failed to expand into the vascular area. This resulted in vessels with reduced or split lumen and open sheets of ECs. Concomitantly, the organization of hematopoietic cells-identified by the presence of previously undescribed membrane tubules-between DA and PCV, and within the vessels, was severely disturbed. Strikingly, ectopic cell junctions occurred across the obstructed vessel lumen, on the luminal EC surfaces, which in control conditions never display junctions of any kind. These data suggest that Egfl7 provides ECs with a cue for their extension into the vascular area and in establishing EC cell polarity. Developmental Dynamics 237:580 -591, 2008.

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Egfl7, a novel epidermal growth factor‐domain gene expressed in endothelial cells

Cited by 152 publications

References 41 publications

Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells

Ectopic expression of miR-126*, an intronic product of the vascular endothelial EGF-like 7 gene, regulates prostein translation and invasiveness of prostate cancer LNCaP cells

EGFL7 Is a Chemoattractant for Endothelial Cells and Is Up-Regulated in Angiogenesis and Arterial Injury

Egfl7 knockdown causes defects in the extension and junctional arrangements of endothelial cells during zebrafish vasculogenesis

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