Regeneration of the endothelium in vascular injury

The endothelium mediates relaxations (dilatations) of the underlying vascular smooth muscle cells. The endothelium-dependent relaxations are due to the release of non-prostanoid vasodilator substances. The best characterized endothelium-derived relaxing factor (EDRF) is nitric oxide (NO). The endothelial cells also release substances (endothelium-derived hyperpolarizing factor, EDHF) that cause hyperpolarization of the cell membrane of the underlying vascular smooth muscle. The release of EDRF from the endothelium can be mediated by both pertussis toxin-sensitive Gi (alpha2-adrenergic activation, serotonin, thrombin) and insensitive Gq (adenosine diphosphate, bradykinin) coupling proteins. The ability of the endothelial cell to release relaxing factors can be upregulated by impregnation with estrogens, exercise and antioxidants, and down-regulated by oxidative stress and increased presence of oxidized LDL. Following injury or apoptotic death, the endothelium regenerates. However, in regenerated endothelial cells, there is an early selective loss of the pertussis-toxin sensitive mechanisms of EDRF-release. Functional studies suggest that abnormal handling of LDL because of increased oxidative stress play a key role in this selective loss. Genomic analysis demonstrates the emergence of fatty acid binding protein-A (A-FBP) and metalloproteinase-7 (MMP7) in regenerated endothelial cells. The reduced release of NO resulting from the endothelial dysfunction in regenerated areas creates a locus minoris resistentiae which favors the occurrence of vasospasm and thrombosis as well as the initiation of atherosclerosis. © Springer Science+Business Media, LLC 2010.postprin

COX-mediated endothelium-dependent contractions: From the past to recent discoveries

Endothelial cells release various substances to control the tone of the underlying vascular smooth muscle. Nitric oxide (NO) is the best defined endothelium-derived relaxing factor (EDRF). Endothelial cells can also increase vascular tone by releasing endothelium-derived contracting factors (EDCF). The over-production of EDCF contributes to the endothelial dysfunctions which accompanies various vascular diseases. The present review summarizes and discusses the mechanisms leading to the release of EDCFs derived from the metabolism of arachidonic acid. This release can be triggered by agonists such as acetylcholine, adenosine nucleotides or by stretch. All these stimuli are able to induce calcium influx into the endothelial cells, an effect which can be mimicked by calcium ionophores. The augmentation in intracellular calcium ion concentration initiates the release of EDCF. Downstream processes include activation of phospholipase A 2 (PLA2), cyclooxygenases (COX) and the production of reactive oxygen species (ROS) and vasoconstrictor prostanoids (endoperoxides, prostacyclin, thromboxane A2 and other prostaglandins) which subsequently diffuse to, and activate thromboxane- prostanoid (TP) receptors on the vascular smooth muscle cells leading to contraction. © 2010 CPS and SIMM All rights reserved.postprin

EDHF: An update

The endothelium controls vascular tone not only by releasing NO and prostacyclin, but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the term 'endothelium-derived hyperpolarizing factor' (EDHF). However, this acronym includes different mechanisms. Arachidonic acid metabolites derived from the cyclo-oxygenases, lipoxygenases and cytochrome P450 pathways, H 2O 2, CO, H 2S and various peptides can be released by endothelial cells. These factors activate different families of K + channels and hyperpolarization of the vascular smooth muscle cells contribute to the mechanisms leading to their relaxation. Additionally, another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells contributes also to endothelium-dependent relaxations (EDHF-mediated responses). These responses involve an increase in the intracellular Ca 2+ concentration of the endothelial cells, followed by the opening of SK Ca and IK Ca channels (small and intermediate conductance Ca 2+-activated K + channels respectively). These channels have a distinct subcellular distribution: SK Ca are widely distributed over the plasma membrane, whereas IK Ca are preferentially expressed in the endothelial projections toward the smooth muscle cells. Following SK Ca activation, smooth muscle hyperpolarization is preferentially evoked by electrical coupling through myoendothelial gap junctions, whereas, following IK Ca activation, K + efflux can activate smooth muscle Kir2.1 and/or Na +/ K +-ATPase. EDHF-mediated responses are altered by aging and various pathologies. Therapeutic interventions can restore these responses, suggesting that the improvement in the EDHF pathway contributes to their beneficial effect. A better characterization of EDHF-mediated responses should allow the determination of whether or not new drugable targets can be identified for the treatment of cardiovascular diseases. © The Authors Journal compilation © 2009 Biochemical Society.postprin

Endothelial dysfunction: A strategic target in the treatment of hypertension?

Endothelial dysfunction is a common feature of hypertension, and it results from the imbalanced release of endothelium-derived relaxing factors (EDRFs; in particular, nitric oxide) and endothelium-derived contracting factors (EDCFs; angiotensin II, endothelins, uridine adenosine tetraphosphate, and cyclooxygenase-derived EDCFs). Thus, drugs that increase EDRFs (using direct nitric oxide releasing compounds, tetrahydrobiopterin, or l-arginine supplementation) or decrease EDCF release or actions (using cyclooxygenase inhibitor or thromboxane A2/prostanoid receptor antagonists) would prevent the dysfunction. Many conventional antihypertensive drugs, including angiotensin-converting enzyme inhibitors, calcium channel blockers, and third-generation β-blockers, possess the ability to reverse endothelial dysfunction. Their use is attractive, as they can address arterial blood pressure and vascular tone simultaneously. The severity of endothelial dysfunction correlates with the development of coronary artery disease and predicts future cardiovascular events. Thus, endothelial dysfunction needs to be considered as a strategic target in the treatment of hypertension. © 2010 Springer-Verlag.postprin

Cellular signaling and NO production

The endothelium can evoke relaxations (dilatations) of the underlying vascular smooth muscle, by releasing vasodilator substances. The best characterized endothelium-derived relaxing factor is nitric oxide (NO), which is synthesized by the endothelial isoform of nitric oxide synthase (eNOS). Endothelium-dependent relaxations involve both pertussis-toxin-sensitive G i (e.g., responses to serotonin, sphingosine 1-phosphate, alpha 2-adrenergic agonists, and thrombin) and pertussis-toxin-insensitive Gq (e.g., adenosine diphosphate and bradykinin) coupling proteins. eNOS undergoes a complex pattern of intracellular regulation, including post-translational modifications involving enzyme acylation and phosphorylation. eNOS is reversibly targeted to signal-transducing plasmalemmal caveolae where the enzyme interacts with a number of regulatory proteins, many of which are modified in cardiovascular disease states. The release of nitric oxide by the endothelial cell can be up- (e.g., by estrogens, exercise, and dietary factors) and down-regulated (e.g. oxidative stress, smoking, and oxidized low-density lipoproteins). It is reduced in the course of vascular disease (e.g., diabetes and hypertension). Arteries covered with regenerated endothelium (e.g. following angioplasty) selectively lose the pertussis-toxin-sensitive pathway for NO release which favors vasospasm, thrombosis, penetration of macrophages, cellular growth, and the inflammatory reaction leading to atherosclerosis. The unraveling of the complex interaction of the pathways regulating the presence and the activity of eNOS will enhance the understanding of the perturbations in endothelium-dependent signaling that are seen in cardiovascular disease states, and may lead to the identification of novel targets for therapeutic intervention. © 2010 Springer-Verlag.postprin

Repressor activator protein 1 induces pro-inflammatory cytokines production in macrophages through NFKB signaling

Abstracts for Oral Presentation: no. OP-5This journal issue including abstracts of 18th Annual Scientific Meeting Institute of Cardiovascular Science and MedicineOBJECTIVES: Repressor activator protein 1 (Rap1), an established telomere-associated protein migrates to the cytoplasm and activates nuclear factor kappa B (NFκB) in human carcinoma cell lines. The present study tested the hypothesis that Rap1 induces production of pro-inflammatory cytokines via NFκB signaling in macrophages, a cell type involved in the development and ...postprin

SIRT1 and AMPK in regulating mammalian senescence: A critical review and a working model

Ageing in mammals remains an unsolved mystery. Anti-ageing is a recurring topic in the history of scientific research. Lifespan extension evoked by Sir2 protein in lower organisms has attracted a large amount of interests in the last decade. This review summarizes recent evidence supporting the role of a Sir2 mammalian homologue, SIRT1 (Silent information regulator T1), in regulating ageing and cellular senescence. The various signaling networks responsible for the anti-ageing and anti-senescence activity of SIRT1 have been discussed. In particular, a counter-balancing model involving the cross-talks between SIRT1 and AMP-activated protein kinase (AMPK), another stress and energy sensor, is suggested for controlling the senescence program in mammalian © 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reservedcells.postprin

Contractions to endogenous and exogenous endothelin-1 in segmental renal arteries of the mouse: up-regulation in obesity

Poster Session 1: Oncology, Renal Physiology and Disease, Neurology, Infectious Diseases, New Topics of Endothelin Biology: P-26Endothelin-1 (ET-1) is implicated in cardiovascular risk factors such as obesity, and the endothelin system is prominent in the kidney. In murine arteries, the contractile pro! le of the peptide is heterogeneous among different preparations, and the renal vascular bed is largely unexplored. Segmental renal arteries branching from the main renal arteries of age-matched lean and 30 weeks diet-induced obese WT mice were investigated by isometric tension recording in Halpern-Mulvany myographs. Contractions after administration of big endothelin-1 (bET-1) or ET-1 (both 10 pM to 100nM) were determined in the absence ...postprin

Vasoconstrictor prostanoids

In cardiovascular diseases and during aging, endothelial dysfunction is due in part to the release of endothelium-derived contracting factors that counteract the vasodilator effect of the nitric oxide. Endotheliumdependent contractions involve the activation of endothelial cyclooxygenases and the release of various prostanoids, which activate thromboxane prostanoid (TP) receptors of the underlying vascular smooth muscle. The stimulation of TP receptors elicits not only the contraction and the proliferation of vascular smooth muscle cells but also diverse physiological/pathophysiological reactions, including platelet aggregation and activation of endothelial inflammatory responses. TP receptor antagonists curtail endothelial dysfunction in diseases such as hypertension and diabetes, are potent antithrombotic agents, and prevent vascular inflammation. © Springer-Verlag 2009.postprin

Arterial endothelial cells: still the craftsmen of regenerated endothelium

For more than a decade, a prevailing hypothesis in research related to arterial disease has been that circulating endothelial progenitor cells (EPCs) provide protection by their innate ability to replace dysfunctional or damaged endothelium. This paradigm has led to extensive investigation of EPCs in the hope of finding therapeutic targets to control their homing and differentiation. However, from the very beginning, the nomenclature and the phenotype of EPCs have been subject to controversy and there are currently no specific markers that can unambiguously identify these cells. Moreover, many of the initial observations that EPCs differentiate to endothelial cells in the course of arterial disease have been criticized for methodological problems. The present review discusses the contrasting experimental evidence as to the role of EPCs in contributing to relining of the endothelium and highlights some of the methodological pitfalls and terminological ambiguities that confuse the field.postprin