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ability leading to vascular leak is an important consequence of sepsis and sepsis-induced lung injury. We previously reported that heat shock protein (hsp) 90 inhibitor pretreatment improved pulmonary barrier dysfunction in a murine model of sepsis-induced lung injury. We now examine the effects of hsp90 inhibitors on LPS-mediated endothelial hyperpermeability, as reflected in changes in transendothelial electrical resistance (TER) of bovine pulmonary arterial endothelial cells (BPAEC). Vehicle-pretreated cells exposed to endotoxin exhibited a concentration-dependent decrease in TER, activation of pp60 Src , phosphorylation of the focal adhesion protein paxillin, and reduced expression of the adherens junction proteins, vascular endothelial (VE)-cadherin and ␤-catenin. Pretreatment with the hsp90 inhibitor, radicicol, prevented the decrease in TER, maintained VEcadherin and ␤-catenin expression, and inhibited activation of pp60 Src and phosphorylation of paxillin. Similarly, when BPAEC hyperpermeability was induced by endotoxin-activated neutrophils, pretreatment of neutrophils and/or endothelial cells with radicicol protected against the activated neutrophil-induced decrease in TER. Increased paxillin phosphorylation and decreased expression of ␤-catenin and VE-cadherin were also observed in mouse lungs 12 h after intraperitoneal endotoxin and attenuated in mice pretreated with radicicol. These results suggest that hsp90 plays an important role in sepsisassociated endothelial barrier dysfunction. endothelial permeability; radicicol; endotoxin; acute respiratory distress syndrome GRAM-NEGATIVE BACTERIAL SEPSIS affects more than 750,000 people annually in the United States alone (31); it is often associated with endothelial hyperpermeability leading to vascular leak syndromes, including acute respiratory distress syndrome (ARDS; Refs. 32, 44). Endotoxin or LPS, the bacterial cell envelope component responsible for most of the septic response, activates macrophages, neutrophils, and other cells to produce inflammatory mediators and free radicals that cause endothelial damage (25). Direct activation of endothelial cells by LPS is one of the earliest causes of endothelial dysfunction in sepsis (3,19).Heat shock protein 90 (hsp90), an abundant molecular chaperone, is involved with folding, maturation, and stabilization of numerous client proteins ranging from tyrosine kinases to several different types of transcription factors and proteins controlling growth and survival (49). Hsp90 inhibitors, such as radicicol, interact with the NH 2 -terminal ATP binding site of hsp90 and result in destabilization and degradation of client proteins (47). Hsp90 inhibitors have emerged as an attractive therapeutic modality for various types of cancer, causing combinatorial blockade of numerous growth-promoting and apoptosis-blocking pathways (45, 55).Regulation of endothelial permeability is a complex process involving signaling components that are associated with cytoskeletal and membrane-bound proteins that maintain cell-cell or c...

The ability to get and keep an erection is important to men for several reasons and the inability is known as erectile dysfunction (ED). ED has started to be accepted as an early indicator of systemic endothelial dysfunction and subsequently of cardiovascular diseases. The role of NO in endothelial relaxation and erectile function is well accepted. The discovery of NO as a small signalling gasotransmitter led to the investigation of the role of other endogenously derived gases, carbon monoxide (CO) and hydrogen sulphide (H2S) in physiological and pathophysiological conditions. The role of NO and CO in sexual function and dysfunction has been investigated more extensively and, recently, the involvement of H2S in erectile function has also been confirmed. In this review, we focus on the role of these three sister gasotransmitters in the physiology, pharmacology and pathophysiology of sexual function in man, specifically erectile function. We have also reviewed the role of soluble guanylyl cyclase/cGMP pathway as a common target of these gasotransmitters. Several studies have proposed alternative therapies targeting different mechanisms in addition to PDE‐5 inhibition for ED treatment, since some patients do not respond to these drugs. This review highlights complementary and possible coordinated roles for these mediators and treatments targeting these gasotransmitters in erectile function/ED. Linked Articles This article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-6

Prevention of cardiovascular disease (CVD) remains one of the largest public health challenges of our time. Identifying individuals at increased cardiovascular risk at an asymptomatic, subclinical stage is of paramount importance for minimizing disease progression as well as the substantial health and economic burden associated with overt CVD. Vascular ageing (VA) involves the deterioration in vascular structure and function over time, and ultimately leads to damage in the heart, brain, kidney, and other organs. VA encompasses the cumulative effect of all cardiovascular risk factors on the arterial wall over the life course and thus may help identify those at elevated cardiovascular risk, early in disease development. Although the concept of VA is gaining interest clinically, it is seldom measured in routine clinical practice due to lack of consensus on how to characterise VA as physiological versus pathological and various practical issues. In this state-of-the-art review and as a network of scientists, clinicians, engineers and industry partners with expertise in VA, we address six questions related to VA in an attempt to increase knowledge among the broader medical community and move the routine measurement of VA a little closer from bench towards bedside.

Reactive oxygen species (ROS) decreases bioavailability of nitric oxide (NO) and impairs NO-dependent relaxations. Like NO, hydrogen sulfide (HS) is an antioxidant and vasodilator; however, the effect of ROS on HS-induced relaxations is unknown. Here we investigated whether ROS altered the effect of HS on vascular tone in mouse aorta and determined whether resveratrol (RVT) protects it via HS. Pyrogallol induced ROS formation. It also decreased HS formation and relaxation induced by l-cysteine and in mouse aorta. Pyrogallol did not alter sodium hydrogensulfide (NaHS)-induced relaxation suggesting that the pyrogallol effect on l-cysteine relaxations was due to endogenous HS formation. RVT inhibited ROS formation, enhanced l-cysteine-induced relaxations and increased HS level in aortas exposed to pyrogallol suggesting that RVT protects against "HS-dysfunctions" by inducing HS formation. Indeed, HS synthesis inhibitor AOAA inhibited the protective effects of RVT. RVT had no effect on Ach-induced relaxation that is NO dependent and the stimulatory effect of RVT on HS-dependent relaxation was also independent of NO. These results demonstrate that oxidative stress impairs endogenous HS-induced relaxations and RVT offers protection by inducing HS suggesting that targeting endogenous HS pathway may prevent vascular dysfunctions associated by oxidative stress.