Transcriptional regulation of the CRLR gene in human microvascular endothelial cells by hypoxia

Nikitenko, Leonid L.; Smith, David M.; Bicknell, Roy; Rees, Margaret

doi:10.1096/fj.02-0993fje

Cited by 71 publications

(60 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The HIF target adrenomedullin was shown to promote physiological and pathological angiogenesis in vitro and in animal models (49)(50)(51). ADM signals angiogenesis by binding calcitonin-receptor-like receptor, which is widely expressed on normal and hypoxic endothelial cells (49,52). Angiogenin was another molecule previously demonstrated to be angiogenic, yet without consequence in TetON-HIF-1:VEGF Δ mice (28,29).…”

Section: Discussionmentioning

confidence: 99%

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

Oladipupo¹,

Kovalski³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

156

113

View full text Add to dashboard Cite

Although our understanding of the molecular regulation of adult neovascularization has advanced tremendously, vascular-targeted therapies for tissue ischemia remain suboptimal. The master regulatory transcription factors of the hypoxia-inducible factor (HIF) family are attractive therapeutic targets because they coordinately up-regulate multiple genes controlling neovascularization. Here, we used an inducible model of epithelial HIF-1 activation, the TetON-HIF-1 mouse, to test the requirement for VEGF in HIF-1 mediated neovascularization. TetON-HIF-1, K14-Cre, and VEGF flox/flox alleles were combined to create TetON-HIF-1:VEGF Δ mice to activate HIF-1 and its target genes in adult basal keratinocytes in the absence of concomitant VEGF. HIF-1 induction failed to produce neovascularization in TetON-HIF-1:VEGF Δ mice despite robust up-regulation of multiple proangiogenic HIF targets, including PlGF, adrenomedullin, angiogenin, and PAI-1. In contrast, endothelial sprouting was preserved, enhanced, and more persistent, consistent with marked reduction in Dll4-Notch-1 signaling. Optical-resolution photoacoustic microscopy, which provides noninvasive, label-free, high resolution, and wide-field vascular imaging, revealed the absence of both capillary expansion and arteriovenous remodeling in serially imaged individual TetON-HIF-1:VEGF Δ mice. Impaired TetON-HIF-1:VEGF Δ neovascularization could be partially rescued by 12- O -tetradecanoylphorbol-13-acetate skin treatment. These data suggest that therapeutic angiogenesis for ischemic cardiovascular disease may require treatment with both HIF-1 and VEGF.

show abstract

Section: Discussionmentioning

confidence: 99%

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

Oladipupo¹,

Kovalski³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

156

113

View full text Add to dashboard Cite

show abstract

“…Associated over-expressed hypoxia-or VEGF-inducible genes for cell-surface receptors included the PDGF-b receptor (Lafuente et al 1999), the endothelial receptor tyrosine kinase, Tie-1 (McCarthy et al 1998), and the calcitonin receptor-like receptor which, together with the receptor activity-modifying proteins, form integral components of the adrenomedullin-signaling system (Nikitenko et al 2003).…”

Section: Discussionmentioning

confidence: 99%

Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel–Lindau syndrome

Eisenhofer

Huynh²,

Pacák³

et al. 2004

Endocr Relat Cancer

187

139

View full text Add to dashboard Cite

Pheochromocytomas in von Hippel-Lindau (VHL) syndrome produce exclusively norepinephrine, whereas those in multiple endocrine neoplasia type 2 (MEN 2) produce epinephrine. This study examined the pathways activated in VHL-associated pheochromocytomas by comparing gene expression profiles in VHL and MEN 2 tumors in relationship to profiles in sporadic norepinephrineand epinephrine-producing tumors. Larger and more distinct differences in gene expression among hereditary than sporadic tumors indicated the importance of the underlying mutation to gene expression profiles. Many of the genes over-expressed in VHL compared with MEN 2 tumors were clearly linked to the hypoxia-driven angiogenic pathways that are activated in VHL-associated tumorigenesis. Such genes included those for the glucose transporter, vascular endothelial growth factor (VEGF), placental growth factor, angiopoietin 2, tie-1, VEGF receptor 2 and its coreceptor, neuropilin-1. Other up-regulated genes, such as connective tissue growth factor, cysteine-rich 61, matrix metalloproteinase 1, vascular endothelial cadherin, tenascin C, stanniocalcin 1, and cyclooxygenases 1 and 2 are known to be involved in VEGF-regulated angiogenesis. Shared differences in expression of subsets of genes in norepinephrine-versus epinephrine-producing hereditary and sporadic pheochromocytomas indicated other differences in gene expression that may underlie the biochemical phenotype. Over-expression of the hypoxia-inducible transcription factor, HIF-2a, in norepinephrine-predominant sporadic and VHL tumors compared with epinephrine-producing tumors indicates that expression of this gene depends on the noradrenergic biochemical phenotype. The findings fit with the known expression of HIF-2a in norepinephrine-producing cells of the sympathetic nervous system and might explain both the development and noradrenergic biochemical phenotype of pheochromocytomas in VHL syndrome.

show abstract

“…Therefore, ADM, through its receptor, may be a factor of importance in regulating synovium homeostasis. Further studies should focus on interactions linking HIF-1, ADM, and CRLR/RAMP-2 during hypoxia, which is the rule in RA synovial tissues (41).…”

Section: Discussionmentioning

confidence: 99%

“…The mechanisms of CRLR/RAMP-2 regulation in cultured RA-FLS are currently under investigation, but some evidence can already be found in the literature. Binding elements for transcription factors such as Sp-1, Pit-1, glucocorticoid receptor, and HIF-1␣ have been found in the human CRLR gene (41), and glucocorticoids are known to increase CRLR mRNA in vascular smooth muscle cells (VSMC) (44). Hypoxia increases CRLR expression in human VSMC from coronary arteries (45).…”

Section: Discussionmentioning

confidence: 99%

A Critical Role for Adrenomedullin-Calcitonin Receptor-Like Receptor in Regulating Rheumatoid Fibroblast-Like Synoviocyte Apoptosis

Uzan

Launay

et al. 2006

The Journal of Immunology

View full text Add to dashboard Cite

Rheumatoid arthritis (RA) is characterized by fibroblast-like synoviocyte (FLS) hyperplasia, which is partly ascribable to decreased apoptosis. In this study, we show that adrenomedullin (ADM), an antiapoptotic peptide, is constitutively secreted in larger amounts by FLS from joints with RA (RA-FLS) than with osteoarthritis (OA-FLS). ADM secretion was regulated by TNF-α. Peptidylglycine α-amidating monooxygenase, the ADM-processing enzyme, was expressed at the mRNA level by both RA-FLS and OA-FLS. Constituents of the ADM heterodimeric receptor calcitonin receptor-like receptor (CRLR)/receptor activity-modifying protein (RAMP)-2 were up-regulated at the mRNA and protein levels in cultured RA-FLS compared with OA-FLS. ADM induced rapid intracellular cAMP production in FLS and reduced caspase-3 activity, DNA fragmentation, and chromatin condensation in RA-FLS exposed to apoptotic conditions, indicating that CRLR/RAMP-2 was fully functional. ADM-induced cAMP production was less marked in OA-FLS than in RA-FLS, suggesting differences in receptor regulation and expression. ADM dose-dependently inhibited RA-FLS apoptosis, and this effect was reversed by the 22–52 ADM antagonist peptide. ADM inhibited RA-FLS apoptosis triggered by extrinsic and intrinsic pathways. Our data suggest that ADM may prevent or reduce RA-FLS apoptosis, via up-regulation of its functional receptor CRLR/RAMP-2. Regulation of ADM secretion and/or CRLR/RAMP-2 activation may constitute new treatment strategies for RA.

show abstract

Transcriptional regulation of the CRLR gene in human microvascular endothelial cells by hypoxia

Cited by 71 publications

References 55 publications

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

VEGF is essential for hypoxia-inducible factor-mediated neovascularization but dispensable for endothelial sprouting

Distinct gene expression profiles in norepinephrine- and epinephrine-producing hereditary and sporadic pheochromocytomas: activation of hypoxia-driven angiogenic pathways in von Hippel–Lindau syndrome

A Critical Role for Adrenomedullin-Calcitonin Receptor-Like Receptor in Regulating Rheumatoid Fibroblast-Like Synoviocyte Apoptosis

Contact Info

Product

Resources

About