Knockdown of Caveolin-1 by Antisense Oligonucleotides Impairs Angiogenesis in Vitro and in Vivo

Griffoni, Cristiana; Spisni, Enzo; Santi, Spartaco; Riccio, Massimo; Guarnieri, Tiziana; Tomasi, Vittorio

doi:10.1006/bbrc.2000.3484

Cited by 86 publications

(56 citation statements)

References 23 publications

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“…Caveolin-1 has been reported to be required for EC vascular network formation in a tissue culture model of angiogenesis. 17,19 Furthermore, caveolin-1-null mice exhibit defective postnatal angiogenesis in response to growth factors and in tumor vascular growth, strongly supporting the hypothesis that caveolin-1 is required for angiogenesis in vivo. 18 These results strongly suggest that the VEGF-null CEB model is suitable for the identification of genes that are downstream of VEGF signaling, which are likely to be EC-specific or EC-selective and are involved in VEGF-mediated EC morphogenesis.…”

Section: Vegf-mediated Vascular Morphogenesis Y-s Ng Et Almentioning

confidence: 63%

“…[17][18][19][20][21] In order to confirm the GEM data, semiquantitative RT-PCR analysis (data not shown) and immunostaining were used to compare the expression of some of these genes between wt and VEGF-null CEB. Consistent with the microarray data, the levels of caveolin-1 and endomucin-1 were significantly lower in the EC of VEGF-null CEB than in the wt CEB (Figure 7), whereas the levels of PECAM-1 were comparable.…”

Section: Validation Of the Gem Datamentioning

confidence: 99%

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Identification of genes involved in VEGF-mediated vascular morphogenesis using embryonic stem cell-derived cystic embryoid bodies

Ramsauer

Loureiro

et al. 2004

Laboratory Investigation

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The vasculature forms during development via two processes, vasculogenesis and angiogenesis, in which vessels form de novo from angioblast precursors or as sprouts from pre-existing vessels, respectively. A common and critical aspect of both processes is vascular morphogenesis, which includes branching of endothelial cell cords and lumen formation. Although ample evidence support the central role of vascular endothelial growth factor (VEGF) in both vasculogenesis and angiogenesis, the role of VEGF in vascular morphogenesis is unclear and little is known about the regulation of vascular morphogenesis, in general. We have used the in vitro vessel differentiation system of embryonic stem (ES) cell-derived cystic embryonic bodies (CEB) as a model for studying VEGF-mediated vessel formation. Whereas CEB formed from wild-type ES cells make well-formed vessel-like structures, CEB derived from VEGF-null ES cells contain PECAM-1-positive endothelial cells, but these cells do not participate in vascular morphogenesis. Using gene expression microarray analysis to compare gene expression in these two systems, we have been able to identify many genes and novel ESTs that are downstream of VEGF function, and which may be involved in VEGF-mediated vascular morphogenesis including caveolin-1 and HEY-1. These results support using the CEB model, in combination with gene knockout ES cells, for studying vascular morphogenesis.

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Section: Vegf-mediated Vascular Morphogenesis Y-s Ng Et Almentioning

confidence: 63%

Section: Validation Of the Gem Datamentioning

confidence: 99%

Identification of genes involved in VEGF-mediated vascular morphogenesis using embryonic stem cell-derived cystic embryoid bodies

Ramsauer

Loureiro

et al. 2004

Laboratory Investigation

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“…This idea is supported by a variety of studies showing that caveolin-1 affects capillary formation. We and others have shown recently that antisense-mediated downregulation of caveolin-1 inhibits capillary tubule formation (40,41). Up-regulation of caveolin-1 in microvascular endothelial cells enhances capillary tubule formation via the caveolin-1 scaffolding domain (41).…”

Section: Figmentioning

confidence: 94%

Loss of Caveolin-1 Polarity Impedes Endothelial Cell Polarization and Directional Movement

Beardsley

Fang

Mertz

et al. 2005

Journal of Biological Chemistry

137

140

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The ability of a cell to move requires the asymmetrical organization of cellular activities. To investigate polarized cellular activity in moving endothelial cells, human endothelial cells were incubated in a Dunn chamber to allow migration toward vascular endothelial growth factor. Immunofluorescent staining with a specific antibody against caveolin-1 revealed that caveolin-1 was concentrated at the rear of moving cells. Similarly, monolayer scraping to induce random cell walk resulted in relocation of caveolin-1 to the cell rear. These results suggest that posterior polarization of caveolin-1 is a common feature both for chemotaxis and chemokinesis. Dual immunofluorescent labeling showed that, during cell spreading, caveolin-1 was compacted in the cell center and excluded from nascent focal contacts along the circular lamellipodium, as revealed by integrin ␤ 1 and FAK staining. When cells were migrating, integrin ␤ 1 and FAK appeared at polarized lamellipodia, whereas caveolin-1 was found at the posterior of moving cells. Notably, wherever caveolin-1 was polarized, there was a conspicuous absence of lamellipod protrusion. Transmission electron microscopy showed that caveolae, similar to their marker caveolin-1, were located at the cell center during cell spreading or at the cell rear during cell migration. In contrast to its unphosphorylated form, tyrosine-phosphorylated caveolin-1, upon fibronectin stimulation, was associated with the focal complex molecule phosphopaxillin along the lamellipodia of moving cells. Thus, unphosphorylated and phosphorylated caveolin-1 were located at opposite poles during cell migration. Importantly, loss of caveolin-1 polarity by targeted down-regulation of the protein prevented cell polarization and directional movement. Our present results suggest a potential role of caveolin polarity in lamellipod extension and cell migration.

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“…Adenoviral-mediated caveolin-1 overexpression increased in vitro tube formation. 15 Accordingly, down-regulation of caveolin-1 reduced EC transmigration to serum, 24 capillary like tube formation 15,25 and angiogenesis in the chorioallantoic membrane assay. 25 These discrepant results suggest an ambiguous role for caveolin-1.…”

mentioning

confidence: 99%

Altered Angiogenesis in Caveolin-1 Gene–Deficient Mice Is Restored by Ablation of Endothelial Nitric Oxide Synthase

Morais

Ebrahem

Anand‐Apte

et al. 2012

The American Journal of Pathology

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Caveolin-1 is an essential structural protein of caveolae, specialized plasma membrane organelles highly abundant in endothelial cells, where they regulate multiple functions including angiogenesis. Caveolin-1 exerts a tonic inhibition of endothelial nitric oxide synthase (eNOS) activity. Accordingly, caveolin-1 gene-disrupted mice have enhanced eNOS activity as well as increased systemic nitric oxide (NO) levels. We hypothesized that excess eNOS activity, secondary to caveolin deficiency, would mediate the decreased angiogenesis observed in caveolin-1 gene-disrupted mice. We tested tumor angiogenesis in mice lacking either one or both proteins, using in vitro, ex vivo, and in vivo assays. We show that endothelial cell migration, tube formation, cell sprouting from aortic rings, tumor growth, and angiogenesis are all significantly impaired in both caveolin-1-null and eNOSnull mice. We further show that these parameters were either partially or fully restored in double knockout mice that lack both caveolin-1 and eNOS. Furthermore, the effects of genetic ablation of eNOS are mimicked by the administration of the NOS inhibitor N-nitro-L-arginine methyl ester hydrochloride (L-NAME), including the reversal of the caveolin-1-null mouse angiogenic phenotype. This study is the first to demonstrate the detrimental effects of unregulated eNOS activity on angiogenesis, and shows that impaired tumor angiogenesis in caveolin-1-null mice is, at least in part, the result of enhanced eNOS activity.

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Knockdown of Caveolin-1 by Antisense Oligonucleotides Impairs Angiogenesis in Vitro and in Vivo

Cited by 86 publications

References 23 publications

Identification of genes involved in VEGF-mediated vascular morphogenesis using embryonic stem cell-derived cystic embryoid bodies

Identification of genes involved in VEGF-mediated vascular morphogenesis using embryonic stem cell-derived cystic embryoid bodies

Loss of Caveolin-1 Polarity Impedes Endothelial Cell Polarization and Directional Movement

Altered Angiogenesis in Caveolin-1 Gene–Deficient Mice Is Restored by Ablation of Endothelial Nitric Oxide Synthase

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