Increased Ischemia-Induced Angiogenesis in the Staggerer Mouse, a Mutant of the Nuclear Receptor Rorα

Besnard, Sandrine; Silvestre, Jean‐Sébastien; Duriez, Micheline; Bakouche, Joëlle; Lemaigre-Dubreuil, Yolande; Mariani, Jean; Lévy, Bernard; Tedgui, Alain

doi:10.1161/hh2401.101755

Cited by 41 publications

(38 citation statements)

References 27 publications

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“…However, increased postischemic angiogenesis was observed in the hindlimbs of homozygous staggerer mice, which may suggest ROR␣ as a negative regulator of ischemia-induced angiogenesis. 17 One of the potential explanations of this discrepancy could be differential roles of functional domains of ROR␣ in new vessel formation. We observed here that DBD of ROR␣ was sufficient to induce protein stability as well as transcriptional activation of HIF-1 (supplemental Figure IV).…”

Section: Discussionmentioning

confidence: 99%

“…15,16 In the staggerer mice, angiogenesis is enhanced markedly after ischemia induced by the ligation of the femoral artery. 17 In the vascular system, ROR␣ mRNAs have been detected in human smooth muscle cells (SMCs), endothelial cells (ECs), as well as mammary arteries. 16,18 ROR␣ expression level is significantly decreased in human atherosclerotic plaques, whereas increased expression is observed after treatment with interleukin (IL) 1␤, tumor necrosis factor (TNF) ␣, and lipopolysaccharide (LPS) in both ECs and human aortic SMCs.…”

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confidence: 99%

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Transcriptional Activation of HIF-1 by RORα and its Role in Hypoxia Signaling

Kim

Yoo

Yang

et al. 2008

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Objective-Hypoxia-inducible factor 1␣ (HIF-1␣) is primarily involved in the adapting of cells to changes in oxygen levels, which is essential for normal vascular function. Recently, physiological roles for retinoic acid-related orphan receptor ␣ (ROR␣) have been implicated in cardiovascular diseases such as atherosclerosis. In this study, we have investigated the potential roles of ROR␣ in the hypoxia signaling pathway in connection with activation of HIF-1␣. Key Words: ROR␣ Ⅲ hypoxia Ⅲ HIF-1␣ Ⅲ melatonin Ⅲ vascular endothelial growth factor R etinoic acid receptor-related orphan receptor ␣ (ROR␣; NR1F1) is a member of the steroid/thyroid hormone receptor superfamily of transcriptional factors and is closely related to the retinoic acid receptors. 1,2 ROR␣ exists in 4 isoforms, ROR␣1, ROR␣2, ROR␣3, and ROR␣4 (also known as RZR␣), which are generated by a combination of alternative promoter use and exon splicing of the RORA gene. 2 These isoforms comprise a common DNA-binding domain (DBD) and a putative ligand-binding domain (LBD), but differ by their N-terminal sequences. 3 Melatonin and synthetic thiazolidine diones have been shown to transactivate ROR␣, although these observations need to be clarified. 4,5 Recently, analysis of the crystal structure of the ligand-binding domain of ROR␣ revealed that a ligand is present in the binding pocket. This was identified as cholesterol, suggesting that plasma and intracellular levels of cholesterol may be important in the regulation of transcriptional activity for ROR␣. 6,7 ROR␣ usually binds as a monomer to a ROR response element (RORE) consisting of a half site core AGGTCA motif or as a homodimer to a direct repeat of the core motif separated by 2 base pairs. 1 Putative ROREs have been identified in the promoters, such as human fibrinogen ␤, Apo A-V, Apo A-I, Apo C-III, PPAR␥, and RevErb␣, which may suggest a role of this receptor in lipid metabolism and cardiovascular physiology. 8 -12 However, little is known regarding the internal and external stimuli that regulate the RORA gene expression.ROR␣ functions have been studied with the help of the staggerer (sg/sg) mutant mouse. A spontaneous mutation in the ligand-binding domain induces a frameshift that results in a protein truncated in its C terminus and generates the staggerer phenotype. 13 These animals experience severe cerebellar ataxia caused by massive neurodegeneration of Purkinje cells. 14 Moreover, the phenotype of these mice revealed that ROR␣ is crucially involved in regulating the inflammatory and immune responses and lipid metabolism, which are closely related to vascular disorders such as atherosclerosis. 15,16 In the staggerer mice, angiogenesis is enhanced markedly after ischemia induced by the ligation of the femoral artery. 17 In the vascular system, ROR␣ mRNAs have been detected in human smooth muscle cells (SMCs), endothelial cells (ECs), as well as mammary arteries. 16,18 ROR␣ expression level is significantly decreased in human atherosclerotic plaques, whereas increased expression is observed a...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Transcriptional Activation of HIF-1 by RORα and its Role in Hypoxia Signaling

Kim

Yoo

Yang

et al. 2008

ATVB

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“…6 Femoral artery ligation induces a rapid and transient increase in ROR␣ mRNA in ischemic tissue. In Rora sg/sg mice, angiogenesis is markedly enhanced after ischemia induced by ligation of the femoral artery: capillary density is increased in the ischemic hindlimb, and leg perfusion is improved.…”

Section: Ror␣ and Ischemia-induced Angiogenesismentioning

confidence: 99%

“…In addition, ROR␣ activates the apolipoprotein A-I (apoA-I) and apoC-III gene transcription, 3,4 modulates the vasomotor tone of small resistance arteries, and participates in the regulation of postischemic angiogenesis. 5,6 This review focuses on the link between ROR␣, vascular biology, and cholesterol homeostasis. Interestingly, recent findings suggest that ROR␣ is an intracellular cholesterol target.…”

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The “CholesteROR” Protective Pathway in the Vascular System

Boukhtouche

Mariani

Tedgui

2004

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Abstract-Retinoic acid receptor-related Orphan Receptor ␣ (ROR␣) is a member of the nuclear hormone receptor superfamily. ROR␣ has long been considered as a constitutive activator of transcription in the absence of exogenous ligand; however, cholesterol has recently been identified as a natural ligand of ROR␣. The spontaneous staggerer (sg/sg) mutation is a deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of ROR␣ activity. The homozygous Rora sg/sg mutant mouse, of which the most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes, including several vascular ones; in particular, dysfunction of smooth muscle cells and enhanced susceptibility to atherosclerosis. Moreover, ROR␣ appears to participate in the regulation of plasma cholesterol levels, and has been shown to positively regulate apolipoprotein (apo)A-I and apoC-III gene expression. Yet its activity is regulated by cholesterol itself, making ROR␣ an intracellular cholesterol target. Key Words: ROR␣ Ⅲ cholesterol Ⅲ statins Ⅲ atherosclerosis Ⅲ lipid homeostasis R etinoic acid receptor-related Orphan Receptor ␣ (ROR␣), initially described as an orphan nuclear receptor, has recently been deorphanized by the identification of its natural ligand as cholesterol or a cholesterol derivative. 1,2 ROR␣ has been shown to be implicated in the development and/or differentiation of many tissues, and provides protection against age-related degenerative processes, including atherosclerosis. In addition, ROR␣ activates the apolipoprotein A-I (apoA-I) and apoC-III gene transcription, 3,4 modulates the vasomotor tone of small resistance arteries, and participates in the regulation of postischemic angiogenesis. 5,6 This review focuses on the link between ROR␣, vascular biology, and cholesterol homeostasis. Interestingly, recent findings suggest that ROR␣ is an intracellular cholesterol target. 1

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“…In line with these findings, Mamontova et al (20) reported that staggerer mice, which carry a deletion within ROR␣ gene that prevents the translation of the LBD, develop severe atherosclerosis in response to a high fat diet. Recently, ROR␣ has been shown to be a negative regulator of ischemiainduced angiogenesis (21) and a possible factor in bone metabolism (22). Finally, ROR␣ has been found to be highly expressed in skeletal muscle (5) and to be involved in myogenesis (23).…”

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confidence: 99%