Communication is important to ensure the correct and efficient flow of information, which is required to sustain active social networks. A fine-tuned communication between cells is vital to maintain the homeostasis and function of multicellular or unicellular organisms in a community environment. Although there are different levels of complexity, intercellular communication, in prokaryotes to mammalians, can occur through secreted molecules (either soluble or encapsulated in vesicles), tubular structures connecting close cells or intercellular channels that link the cytoplasm of adjacent cells. In mammals, these different types of communication serve different purposes, may involve distinct factors and are mediated by extracellular vesicles, tunnelling nanotubes or gap junctions. Recent studies have shown that connexin 43 (Cx43, also known as GJA1), a transmembrane protein initially described as a gap junction protein, participates in all these forms of communication; this emphasizes the concept of adopting strategies to maximize the potential of available resources by reutilizing the same factor in different scenarios. In this Review, we provide an overview of the most recent advances regarding the role of Cx43 in intercellular communication mediated by extracellular vesicles, tunnelling nanotubes and gap junctions.

Background and Purpose—: The aim of this study is to assess whether the PHASES score allows to (1) match decisions taken by multidisciplinary team whether to observe or intervene, (2) classify patients being diagnosed with a ruptured versus unruptured intracranial aneurysm (UIA), and (3) discriminate patients at low risk of rupture from the population of patients diagnosed with intracranial aneurysm. Methods—: Population-based prospective and consecutive data were collected between 2006 and 2014. Patients (n=841) were stratified into 4 groups: stable UIA; growing observed UIA; immediately treated UIA; and aneurysmal subarachnoid hemorrhage (aSAH). All patients initially observed were pooled in a follow-up UIA group; patients from growing observed UIA, immediately treated UIA, and aSAH were pooled in a high risk of rupture group. Results are expressed as median [quartile 1, quartile 3]. Results—: PHASES scores of immediately treated UIA patients were significantly higher than follow-up UIA group (5 [3, 7] versus 2 [1, 4]). Patients diagnosed with UIA and PHASES score of >3 were more likely to be treated, and the score ≤3 was predictive for observation (areas under these curves=0.74). Odds of being diagnosed with an aSAH were associated with PHASES score of >3 (UIA, 4 [2, 6]; aSAH, 5 [4, 8]; areas under these curves=0.66). Scores of stable UIA patients were significantly lower than high risk of rupture group (2 [1, 4] versus 5 [4, 7]; stable UIA outcome prediction by PHASES score of ≤3: areas under these curves=0.76). Conclusions—: There is a progression of PHASES score between stable UIA, growing observed UIA, immediately treated UIA, and aSAH groups. PHASES score of ≤3 is associated with a low but not negligible likelihood of aneurysm rupture, and specificity of the classifier is low.

Summary: Obesity, and especially excessive visceral adipose tissue accumulation, is considered as a low-grade inflammatory state that is responsible for adipocyte dysfunction and associated metabolic disorders. Adipose tissue displays endocrine functions by releasing pro- or antiinflammatory bioactive molecules named adipokines. An altered expression of these molecules, provoked by obesity or adipocyte dysregulation, contributes to major metabolic diseases such as insulin resistance and type 2 diabetes mellitus that are important risk factors for cardiovascular disease. However, obesity is also characterised by the expansion of perivascular adipose tissue that acts locally via diffusion of adipokines into the vascular wall. Local inflammation within blood vessels induced by adipokines contributes to the onset of endothelial dysfunction, atherosclerosis and thrombosis, but also to vascular remodelling and hypertension. A fast expansion of obesity is expected in the near future, which will rapidly increase the incidence of these cardiovascular diseases. The focus of this review is to summarise the link between metabolic and cardiovascular disease and discuss current treatment approaches, limitations and future perspectives for more targeted therapies.

The c-Jun NH₂-terminal kinase (JNK) pathway of the mitogen-activated protein kinase (MAPK) signaling cascade regulates cell function and survival after stress stimulation. Equally robust studies reported dichotomous results suggesting both protective and detrimental effects of JNK during myocardial ischemia-reperfusion (I/R). The lack of a highly specific JNK inhibitor contributed to this controversy. We recently developed a cell-penetrating, protease-resistant peptide inhibitor of JNK, d-JNKI-1. Here we report on the effects of d-JNKI-1 in myocardial I/R. d-JNKI-1 was tested in isolated-perfused adult rat hearts. Increased activation of JNK, p38-MAPK, and extracellular signal-regulated kinase-1/2 (ERK1/2), as assessed by kinase assays and Western blotting, occurred during I/R. d-JNKI-1 delivered before onset of ischemia prevented the increase in JNK activity while not affecting ERK1/2 and p38-MAPK activation. JNK inhibition reduced ischemic injury, as manifested by increased time to contracture ( P < 0.05) and decreased left ventricular end-diastolic pressure during ischemia ( P < 0.01), and enhanced posthypoxic recovery of systolic and diastolic function ( P < 0.01). d-JNKI-1 reduced mitochondrial cytochrome- c release, caspase-3 activation, and the number of apoptotic cells determined by terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling ( P < 0.05), indicating suppression of the mitochondrial machinery of apoptosis. d-JNKI-1 delivered at the time of reperfusion did not improve functional recovery but still prevented apoptosis. In vivo, d-JNKI-1 reduced infarct size after coronary artery occlusion and reperfusion by ∼50% ( P < 0.01). In conclusion, d-JNKI-1 is an important compound that can be used in preclinical models to investigate the role of JNK signaling in vivo. Inhibition of JNK during I/R is cardioprotective in anesthetized rats in vivo.

Background: Intracranial aneurysm (IA) is a disease of the vascular wall resulting in abnormal enlargement of the vessel lumen. It is a common pathology with a prevalence of 2%‐3% in the adult population. IAs are mostly small, quiescent and asymptomatic; yet, upon rupture, severe brain damage or even death is frequently encountered. In addition to clinical factors, hemodynamic forces, mainly wall shear stress (WSS), have been associated with the initiation of IAs and possibly with their risk of rupture. However, the mechanism by which WSS contributes to aneurysm growth and rupture is not completely understood.Design: PubMed and Ovid MEDLINE databases were searched. In addition, key review articles were screened for relevant original publications.Results: Current knowledge about the relation between WSS and IA has been obtained from both computational fluid dynamic studies in patients and experimental models of IA formation and growth. It is increasingly recognized that a high wall shear stress (gradient) participates to IA formation and that both low and high WSS can drive IA growth. Primary cilia (PC) play an important role as mechanosensors as patients with polycystic kidney disease, which is characterized by the absence or dysfunction of PC, have increased risk to develop IAs as well as increased risk of rupture.Conclusion: Wall shear stress is a key player in IA initiation and progression. It is involved in vascular wall remodelling and inflammation, processes underlying aneurysm pathophysiology.