Caveolin-1 Deficiency Increases Cerebral Ischemic Injury

Jasmin, Jean-François; Malhotra, Samit; Dhallu, Manjeet; Mercier, Isabelle Le; Rosenbaum, Daniel M.; Lisanti, Michael P.

doi:10.1161/01.res.0000260180.42709.29

Cited by 121 publications

(128 citation statements)

References 35 publications

Supporting

Mentioning

119

Contrasting

Order By: Relevance

“…These results extend those that have shown that the loss of Cav-1, either through siRNA or transgenic models, can blunt neuroprotection (9) and metabotropic glutamate receptor-mediated long-term depression (43,59) and accelerate a neurodegenerative phenotype (32,60,61). Our findings obtained with siRNA-mediated Cav-1 knockdown extend the role of Cav-1 in neuronal signaling to a variety of receptors in addition to glutamate.…”

Section: Syncav1supporting

confidence: 88%

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

Head

Finley

et al. 2011

Journal of Biological Chemistry

113

View full text Add to dashboard Cite

Decreased expression of prosurvival and progrowth-stimulatory pathways, in addition to an environment that inhibits neuronal growth, contribute to the limited regenerative capacity in the central nervous system following injury or neurodegeneration. Membrane/lipid rafts, plasmalemmal microdomains enriched in cholesterol, sphingolipids, and the protein caveolin (Cav) are essential for synaptic development/stabilization and neuronal signaling. Cav-1 concentrates glutamate and neurotrophin receptors and prosurvival kinases and regulates cAMP formation. Here, we show that primary neurons that express a synapsin-driven Cav-1 vector (SynCav1) have increased raft formation, neurotransmitter and neurotrophin receptor expression, NMDA-and BDNF-mediated prosurvival kinase activation, agonist-stimulated cAMP formation, and dendritic growth. Moreover, expression of SynCav1 in Cav-1 KO neurons restores NMDA-and BDNF-mediated signaling and enhances dendritic growth. The enhanced dendritic growth occurred even in the presence of inhibitory cytokines (TNF␣, IL-1␤) and myelin-associated glycoproteins (MAG, Nogo). Targeting of Cav-1 to neurons thus enhances prosurvival and progrowth signaling and may be a novel means to repair the injured and neurodegenerative brain.Multiple signaling pathways have been identified that promote growth and survival of neurons and thereby facilitate the formation of synaptic connections that are essential for learning, memory, and the development of the CNS (1-3). Neurotransmitter and neurotrophic receptors, non-receptor tyrosine kinases, and other signaling mediators aggregate to mold and shape postsynaptic densities to permit high-fidelity signal transduction and the regulation of neuronal function (4 -6). A major non-protein component of synapses is cholesterol, which can be a limiting factor in synapse development, synaptic activity, and transmitter release (7).Increasing evidence shows that membrane/lipid rafts, discrete regions of the plasma membrane enriched in cholesterol, glycosphingolipids, and sphingomyelin organize prosurvival and progrowth neuronal signaling pathways (8 -10), regulate cAMP formation (11), and are essential for synapse development, stabilization, and maintenance (7, 12). Caveolin (Cav), 2 a cholesterol binding protein and scaffolding protein found within membrane/lipid rafts (13), organizes and targets certain neuronal growth-promoting proteins, such as components of the neurotransmitter and neurotrophic receptor signaling pathways, to membrane/lipid rafts. These include NMDA receptors, AMPA receptors, Trk receptors, GPC receptors, and Src family kinases (9, 14 -16). These receptors and signaling molecules can enhance cAMP formation, an essential second messenger for promoting neuronal growth and dendritic arborization (17-21), and are found within membrane/lipid rafts in growth cones (6). In the setting of traumatic brain injury and neurodegenerative disorders, interventions that activate signaling pathways to stimulate cAMP production thus have the potential to improve...

show abstract

Section: Syncav1supporting

confidence: 88%

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

Head

Finley

et al. 2011

Journal of Biological Chemistry

113

View full text Add to dashboard Cite

show abstract

“…Consistent with our findings (Figures 6 and 7), Griffoni et al 26 reported that knockdown of caveolin-1 by antisense oligonucleotides impaired angiogenesis, both in vitro in a fibrin gel assay and in vivo on chicken chorio-allantoic membranes. In addition, Jasmin et al 59 found that ischemic cerebral injury generated an impaired angiogenic response in cav-1 Ϫ/Ϫ mice, and Woodman et al 22 reported decreased angiogenesis induced by basic fibroblast growth factor in Matrigel plugs, and, as reported here (Figure 7), decreased B16 tumor growth and associated angiogenesis. On the other hand, Bauer et al 23 found that angiogenesis induced by Ad-VEGF 164 and by tissue ischemia was significantly impaired in transgenic mice in which caveolin-1 was overexpressed.…”

Section: Discussionsupporting

confidence: 71%

Vascular Permeability and Pathological Angiogenesis in Caveolin-1-Null Mice

Chang

Feng

Nagy

et al. 2009

The American Journal of Pathology

View full text Add to dashboard Cite

Caveolin-1, the signature protein of endothelial cell caveolae, has many important functions in vascular cells. Caveolae are thought to be the transcellular pathway by which plasma proteins cross normal capillary endothelium, but, unexpectedly, cav-1 ؊/؊ mice, which lack caveolae, have increased permeability to plasma albumin. The acute increase in vascular permeability induced by agents such as vascular endothelial growth factor (VEGF)-A occurs through venules, not capillaries, and particularly through the vesiculo-vacuolar organelle (VVO), a unique structure composed of numerous interconnecting vesicles and vacuoles that together span the venular endothelium from lumen to ablumen. Furthermore, the hyperpermeable blood vessels found in pathological angiogenesis, mother vessels, are derived from venules. The present experiments made use of cav-1 ؊/؊ mice to investigate the relationship between caveolae and VVOs and the roles of caveolin-1 in VVO structure in the acute vascular hyperpermeability induced by VEGF-A and in pathological angiogenesis and associated chronic vascular hyperpermeability. We found that VVOs expressed caveolin-1 variably but, in contrast to caveolae, were present in normal numbers and with apparently unaltered structure in cav-1 ؊/؊ mice. Nonetheless, VEGF-A-induced hyperpermeability was strikingly reduced in cav-1 ؊/؊ mice, as was pathological angiogenesis and associated chronic vascular hyperpermeability, whether induced by VEGF-A 164 or by a tumor. Thus, caveolin-1 is not necessary for VVO structure but may have important roles in regulating VVO function in acute vascular hyperpermeability and angiogenesis. (Am J Pathol

show abstract

“…Decreased angiogenesis was shown using bFGF-containing matrigel plugs, 20 VEGF-expressing adenoviral vector, 22 experimental colitis 23 or cerebral ischemia. 37 Reduced ischemic hindlimb reperfusion after femoral artery resection is also apparent in these mice. 21 Defective mobilization of endothelial progenitors in response to ischemia was further documented in caveolin-1-deficient mice.…”

Section: Discussionmentioning

confidence: 87%

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

View full text Add to dashboard Cite

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.

show abstract

Caveolin-1 Deficiency Increases Cerebral Ischemic Injury

Cited by 121 publications

References 35 publications

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

Neuron-targeted Caveolin-1 Protein Enhances Signaling and Promotes Arborization of Primary Neurons

Vascular Permeability and Pathological Angiogenesis in Caveolin-1-Null Mice

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

Contact Info

Product

Resources

About