Caveolin, Caveolae, and Endothelial Cell Function

Frank, Philippe G.; Woodman, Scott E.; Park, David; Lisanti, Michael P.

doi:10.1161/01.atv.0000070546.16946.3a

Cited by 342 publications

(285 citation statements)

References 95 publications

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“…The most common uptake mechanism in endothelial cells is the caveolae‐mediated uptake32 but it has been demonstrated that PAMAM dendrimers are taken up via a clathrin‐mediated pathway 33. To better understand the underlying uptake mechanism, we investigated the couptake of DSA with markers for both pathways.…”

Section: Resultsmentioning

confidence: 99%

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

Moscariello

Jansen

et al. 2018

Advanced Science

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Neurological disorders are undoubtedly among the most alarming diseases humans might face. In treatment of neurological disorders, the blood‐brain barrier (BBB) is a challenging obstacle preventing drug penetration into the brain. Advances in dendrimer chemistry for central nervous system (CNS) treatments are presented here. A poly(amido)amine (PAMAM) dendrimer bioconjugate with a streptavidin adapter for the attachment of dendrons or any biotinylated drug is constructed. In vitro studies on porcine or murine models and in vivo mouse studies are performed and reveal the permeation of dendronized streptavidin (DSA) into the CNS. The bioconjugate is taken up mainly by the caveolae pathway and transported across the BBB via transcytosis escaping from lysosomes. After transcytosis DSA are delivered to astrocytes and neurons. Furthermore, DSA offer high biocompatibility in vitro and in vivo. In summary, a new strategy for implementing therapeutic PAMAM function as well as drug delivery in neuropathology is presented here.

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Section: Resultsmentioning

confidence: 99%

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

Moscariello

Jansen

et al. 2018

Advanced Science

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“…Research on caveolae and caveolin-1 may be of future interest, because endothelial cells exhibit high levels of caveolin-1. Caveolin-1 has been implicated in the regulation of eNOS turnover and consequently in NO release as a result of shear stress (142).…”

Section: New Research On Endotheliummentioning

confidence: 99%

Endothelial Dysfunction

Endemann¹

2004

Journal of the American Society of Nephrology

1,110

834

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Abstract. Endothelial dysfunction is characterized by a shift of the actions of the endothelium toward reduced vasodilation, a proinflammatory state, and prothrombic properties. It is associated with most forms of cardiovascular disease, such as hypertension, coronary artery disease, chronic heart failure, peripheral artery disease, diabetes, and chronic renal failure. Mechanisms that participate in the reduced vasodilatory responses in endothelial dysfunction include reduced nitric oxide generation, oxidative excess, and reduced production of hyperpolarizing factor. Upregulation of adhesion molecules, generation of chemokines such as macrophage chemoattractant peptide-1, and production of plasminogen activator inhibitor-1 participate in the inflammatory response and contribute to a prothrombic state. Vasoactive peptides such as angiotensin II and endothelin-1; the accumulation of asymmetric dimethylarginine, an endogenous nitric oxide inhibitor; hypercholesterolemia; hyperhomocysteinemia; altered insulin signaling; and hyperglycemia can contribute to these different mechanisms. Detachment and apoptosis of endothelial cells (anoikis) are associated phenomena. Endothelial dysfunction is an important early event in the pathogenesis of atherosclerosis, contributing to plaque initiation and progression. Reductions in circulating endothelial progenitor cells that participate in regeneration of the endothelium participate in endothelial pathophysiology. The severity of endothelial dysfunction has been shown to have prognostic value for cardiovascular events.

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“…Endothelial cells are known to express the highest levels of caveolin-1. 76 Virgintino et al 77 have reported that caveolin-1 and -2 are found in rat microvessels, and caveolin-1 is expressed in the human BBB. In the primate BBB, confocal microscopic studies indicate caveolin-1 is found in both endothelium and astrocytes.…”

Section: Caveolin-1 In Bbb Endotheliamentioning

confidence: 99%

“…76 Caveolin, a 21-to 24-kDa protein, is a principal structural component of caveolae, and three caveolin genes (caveolin-1, -2, and -3) have been identified. Endothelial cells are known to express the highest levels of caveolin-1.…”

Section: Caveolin-1 In Bbb Endotheliamentioning

confidence: 99%

“…Molecules such as albumin and insulin are known to undergo endothelial transcytosis in peripheral tissue, perhaps through different subsets of caveolae. 76 If insulin transcytosis at the BBB is similarly via caveolae, the up-or downregulation of caveolin-1 could affect vector-mediated brain drug delivery via the insulin receptor. Coloma et al 80 have shown that the murine 83-14 monoclonal antibody to the human insulin receptor can indeed be used for brain drug targeting of neurotherapeutics that normally do not cross the BBB, and their study suggests that insulin receptor expression is more than adequate for this purpose.…”

Section: Caveolin-1 In Bbb Endotheliamentioning

confidence: 99%

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Localization of brain endothelial luminal and abluminal transporters with immunogold electron microscopy

2005

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Summary:Immunogold electron microscopy has identified a variety of blood-brain barrier (BBB) proteins with transporter and regulatory functions. For example, isoforms of the glucose transporter, protein kinase C (PKC), and caveolin-1 are BBB specific. Isoform 1 of the facilitative glucose transporter family (GLUT1) is expressed solely in endothelial (and pericyte) domains, and ϳ75% of the protein is membrane-localized in humans. Evidence is presented for a water cotransport function of BBB GLUT1. A shift in transporter polarity characterized by increased luminal membrane GLUT1 is seen when BBB glucose transport is upregulated; but a greater abluminal membrane density is seen in the human BBB when GLUT1 is downregulated. PKC colocalizes with GLUT1 within these endothelial domains during up-and downregulation, suggesting that a PKC-mediated mechanism regulates human BBB glucose transporter expression. Occludin and claudin-5 (like other tight-junctional proteins) exhibit a restricted distribution, and are expressed solely within interendothelial clefts of the BBB. GFAP (glial fibrillary acidic protein) is uniformly expressed throughout the foot-processes and the entire astrocyte. But the microvascular-facing membranes of the glial processes that contact the basal laminae are also polarized, and their transporters may also redistribute within the astrocyte. Monocarboxylic acid transporter and water channel (Aquaporin-4) expression are enriched at the glial foot-process, and both undergo physiological modulation. We suggest that as transcytosis and efflux mechanisms generate interest as potential neurotherapeutic targets, electron microscopic confirmation of their site-specific expression patterns will continue to support the CNS drug discovery process.

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Caveolin, Caveolae, and Endothelial Cell Function

Cited by 342 publications

References 95 publications

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

Brain Delivery of Multifunctional Dendrimer Protein Bioconjugates

Endothelial Dysfunction

Localization of brain endothelial luminal and abluminal transporters with immunogold electron microscopy

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