Adventures in vascular biology: a tale of two mediators

Moncada, Salvador

doi:10.1098/rstb.2005.1775

Cited by 99 publications

(69 citation statements)

References 233 publications

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“…Previous studies indicate that PG effects on endothelial permeability and vascular tone may be mediated in part by cAMP-dependent protein kinase [4,46]. However, PKA-independent signaling pathways activated by PGI 2 are much less investigated.…”

Section: Involvement Of Camp and Pka In Pg-induced Rac Activation Andmentioning

confidence: 99%

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Birukova

Zagranichnaya

et al. 2007

Experimental Cell Research

261

267

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Prostaglandin E 2 (PGE 2 ) and prostacyclin are lipid mediators produced by cyclooxygenase and implicated in the regulation of vascular function, wound repair, inflammatory processes, and acute lung injury. Although protective effects of these prostaglandins (PGs) are associated with stimulation of intracellular cAMP production, the crosstalk between cAMP-activated signal pathways in the regulation of endothelial cell (EC) permeability is not well understood. We studied involvement of cAMP-dependent kinase (PKA), cAMP-Epac-Rap1 pathway, and small GTPase Rac in the PGsinduced EC barrier protective effects and cytoskeletal remodeling. PGE 2 and PGI 2 synthetic analog beraprost increased transendothelial electrical resistance and decreased dextran permeability, enhanced peripheral F-actin rim and increased intercellular adherens junction areas reflecting EC barrier-protective response. Furthermore, beraprost dramatically attenuated thrombin-induced Rho activation, MLC phosphorylation and EC barrier dysfunction. In vivo, beraprost attenuated lung barrier dysfunction induced by high tidal volume mechanical ventilation. Both PGs caused cAMPmediated activation of PKA-, Epac/Rap1-and Tiam1/Vav2-dependent pathways of Rac1 activation and EC barrier regulation. Knockdown of Epac, Rap1, Rac-specific exchange factors Tiam1 and Vav2 using siRNA approach, or inhibition of PKA activity decreased Rac1 activation and PGinduced EC barrier enhancement. Thus, our results show that barrier-protective effects of PGE 2 and prostacyclin on pulmonary EC are mediated by PKA and Epac/Rap pathways, which converge on Rac activation and lead to enhancement of peripheral actin cytoskeleton and adherens junctions. These mechanisms may mediate protective effects of PGs against agonist-induced lung vascular barrier dysfunction in vitro and against mechanical stress-induced lung injury in vivo.

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Section: Involvement Of Camp and Pka In Pg-induced Rac Activation Andmentioning

confidence: 99%

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Birukova

Zagranichnaya

et al. 2007

Experimental Cell Research

261

267

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“…Since 1980, when Furchgott & Zawadzki (51) first reported that the vasodilation response to ACh requires the presence of an intact endothelium, the role of the endothelium in the regulation of vascular tone has attracted considerable interest (see 54). Action on endothelial receptors by a number of vasoactive substances stimulates the production of endothelium-derived relaxing factors (EDRF), endothelium-derived hyperpolarizing factor, and endothelium-derived constricting factors (EDCF) (see 50).…”

Section: Endotheliummentioning

confidence: 99%

Autonomic Neurotransmission: 60 Years Since Sir Henry Dale

Burnstock

2009

Annu. Rev. Pharmacol. Toxicol.

109

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In the early twentieth century, Sir Henry Dale and others described brilliant studies of autonomic neurotransmission utilizing acetylcholine and noradrenaline. However, within the past 60 years, new discoveries have changed our understanding of the organization of the autonomic nervous system, including the structure and function of the nonsynaptic autonomic neuroeffector junction, the multiplicity of neurotransmitters, cotransmission, neuromodulation, dual control of vascular tone by perivascular nerves and endothelial cells, the molecular biology of receptors, and trophic signaling. Further, it is now recognized that an outstanding feature of autonomic neurotransmission is the inherent plasticity afforded by its structural and neurochemical organization and the interaction between expression of neural mediators and environmental factors. In this way, autonomic neurotransmission is matched to ongoing changes in demands and can sometimes be compensatory in pathophysiological situations.

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“…When there is sufficient oxygen, the enzyme predominates in its oxidized state while, as the oxygen decreases and becomes limiting, the enzyme is more abundant in its reduced state. The discovery that nitric oxide (NO, a gas that closely resembles oxygen structurally) is an endogenous mediator, 6 together with the later demonstration in in vitro experiments of the interaction between NO and oxygen at the CcO and the fact that this enzyme has a greater affinity for NO than for oxygen [7][8][9] suggested that this interaction might be physiologically relevant. In spite of some controversy 10 there is increasing evidence to suggest that NO and oxygen do interact physiologically at the level of the CcO.…”

mentioning

confidence: 99%

Nitric Oxide, Cytochrome C Oxidase, and the Cellular Response to Hypoxia

Taylor

Moncada²

2010

ATVB

183

109

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Abstract-Cytochrome c oxidase (CcO; complex IV of the mitochondrial electron transport chain) is the primary site of cellular oxygen consumption and, as such, is central to oxidative phosphorylation and the generation of adenosinetriphosphate. Nitric oxide (NO), an endogenously-generated gas, modulates the activity of CcO. Depending on the intracellular oxygen concentration and the resultant dominant redox state of CcO, the interaction between CcO and NO can have a range of signaling consequences for cells in the perception of changes in oxygen concentration and the initiation of adaptive responses. At higher oxygen concentrations, when CcO is predominantly in an oxidized state, it consumes NO. At lower oxygen concentrations, when CcO is predominantly reduced, NO is not consumed and accumulates in the microenvironment, with implications for both the respiratory rate of cells and the local vascular tone. Changes in the availability of intracellular oxygen and in the generation of reactive oxygen species that accompany these interactions result in cell signaling and in regulation of oxygen-sensitive pathways that ultimately determine the nature of the cellular response to hypoxia. (Arterioscler Thromb Vasc Biol. 2010;30:643-647.)Key Words: nitric oxide Ⅲ reactive oxygen species Ⅲ cytochrome oxidase Ⅲ hypoxia Ⅲ mitochondria O xygen arose in the earth's atmosphere some 2.3 billion years ago as a by-product generated by photosynthesizing cyanobacteria in the oceans of the planet. 1 Hypotheses suggest that the accumulating presence of this colorless, odorless, but highly reactive molecule initially represented a major threat to life on earth. However, an endosymbiotic relationship that developed between 2 primitive cell types during this time led to the evolution of a unicellular organism which was not only resistant to the oxidizing properties of oxygen but could use them in the generation of energy through catalyzing the efficient oxidative metabolism of sugars, such as glucose, and fatty acids. 2,3 The key to this development was the incorporation of oxygen-consuming bacteria into the host cytoplasm, leading to the evolution of what have become mitochondria. Such was the increase in efficiency afforded by the use of oxygen as a substrate for the production of adenosine-triphosphate (ATP) that it enabled the rapid development of multicellular forms of life that were totally dependent on the utilization of this gas for some of their key metabolic processes. 4 It is not surprising, therefore, that during the course of evolution, molecular mechanisms have developed to respond to low oxygen concentrations [O 2 ] with the induction of a transcriptional response directed toward hypoxic adaptation. It has recently become clear that mitochondria play a critical role in determining the activation of this response. Interaction Between Nitric Oxide and Cytochrome C OxidaseMitochondria produce ATP constantly and are therefore permanently active. The proton gradient that drives the ATP synthase (which generates the majority of ...

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Adventures in vascular biology: a tale of two mediators

Cited by 99 publications

References 233 publications

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Prostaglandins PGE2 and PGI2 promote endothelial barrier enhancement via PKA- and Epac1/Rap1-dependent Rac activation

Autonomic Neurotransmission: 60 Years Since Sir Henry Dale

Nitric Oxide, Cytochrome C Oxidase, and the Cellular Response to Hypoxia

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