Interaction between integrin α5 and PDE4D regulates endothelial inflammatory signalling

Atherosclerosis is primarily a disease of lipid metabolism and inflammation; however, it is also closely associated with endothelial extracellular matrix (ECM) remodelling, with fibronectin accumulating in the laminin–collagen basement membrane. To investigate how fibronectin modulates inflammation in arteries, we replaced the cytoplasmic tail of the fibronectin receptor integrin α5 with that of the collagen/laminin receptor integrin α2. This chimaera suppressed inflammatory signalling in endothelial cells on fibronectin and in knock-in mice. Fibronectin promoted inflammation by suppressing anti-inflammatory cAMP. cAMP was activated through endothelial prostacyclin secretion; however, this was ECM-independent. Instead, cells on fibronectin suppressed cAMP via enhanced phosphodiesterase (PDE) activity, through direct binding of integrin α5 to phosphodiesterase-4D5 (PDE4D5), which induced PP2A-dependent dephosphorylation of PDE4D5 on the inhibitory site Ser651. In vivo knockdown of PDE4D5 inhibited inflammation at athero-prone sites. These data elucidate a molecular mechanism linking ECM remodelling and inflammation, thereby identifying a new class of therapeutic targets.United States. National Institutes of Health (5R01HL75092)National Science Foundation (U.S.). Materials Research Science and Engineering Centers (Program) (MR/J007412/1

Blood flow modulation of vascular dynamics

Purpose of review: Blood flow is intimately linked with cardiovascular development, repair and dysfunction. The current review will build on the fluid mechanical principle underlying haemodynamic shear forces, mechanotransduction and metabolic effects. Recent findings: Pulsatile flow produces both time (∂τ/∂t) and spatial-varying shear stress (∂τ/∂x) to modulate vascular oxidative stress and inflammatory response with pathophysiological significance to atherosclerosis. The characteristics of haemodynamic shear forces, namely, steady laminar (∂τ/∂t = 0), pulsatile shear stress (PSS: unidirectional forward flow) and oscillatory shear stress (bidirectional with a near net 0 forward flow), modulate mechano-signal transduction to influence metabolic effects on vascular endothelial function. Atheroprotective PSS promotes antioxidant, anti-inflammatory and antithrombotic responses, whereas atherogenic oscillatory shear stress induces nicotinamide adenine dinucleotide phosphate oxidase–JNK signalling to increase mitochondrial superoxide production, protein degradation of manganese superoxide dismutase and post-translational protein modifications of LDL particles in the disturbed flow-exposed regions of vasculature. In the era of tissue regeneration, shear stress has been implicated in reactivation of developmental genes, namely, Wnt and Notch signalling, for vascular development and repair. Summary: Blood flow imparts a dynamic continuum from vascular development to repair. Augmentation of PSS confers atheroprotection and reactivation of developmental signalling pathways for regeneration

Astrocyte involvement in blood–brain barrier function: a critical update highlighting novel, complex, neurovascular interactions

Neurological disorders have been linked to a defective blood–brain barrier (BBB), with dysfunctions triggered by stage-specific disease mechanisms, some of these being generated through interactions in the neurovascular unit (NVU). Advanced knowledge of molecular and signaling mechanisms in the NVU and the emergence of improved experimental models allow BBB permeability prediction and the development of new brain-targeted therapies. As NVU constituents, astrocytes are the most numerous glial cells, characterized by a heterogeneity that occurs as a result of developmental and context-based gene expression profiles and the differential expression of non-coding ribonucleic acids (RNAs). Due to their heterogeneity and dynamic responses to different signals, astrocytes may have a beneficial or detrimental role in the BBB’s barrier function, with deep effects on the pathophysiology of (and on the progression of) central nervous system diseases. The implication of astrocytic-derived extracellular vesicles in pathological mechanisms, due to their ability to pass the BBB, must also be considered. The molecular mechanisms of astrocytes’ interaction with endothelial cells at the BBB level are considered promising therapeutic targets in different neurological conditions. Nevertheless, a personalized and well-founded approach must be addressed, due to the temporal and spatial heterogeneity of reactive astrogliosis states during disease

Bench-to-bedside review: the role of activated protein C in maintaining endothelial tight junction function and its relationship to organ injury.

Activated protein C (APC) has emerged as a novel therapeutic agent for use in selected patients with severe sepsis, even though the mechanism of its benefit is not well established. APC has anticoagulant, anti-inflammatory, antiapoptotic, and profibrinolytic properties, but it is not clear through which of these mechanisms APC exerts its benefit in severe sepsis. Focus has recently turned to the role of APC in maintaining endothelial barrier function, and in vitro and in vivo studies have examined this relationship. This article critically reviews these studies, with a focus on potential mechanisms of action

Neuroprotection Caused by Hyperoxia Preconditioning in Animal Stroke Models

Ischemic tolerance induced by hyperoxia (HO) can protect against brain injury and neurodegenerative diseases. Although multiple studies demonstrate neuroprotection by HO, the exact mechanism(s) of HO neuroprotection has not been elucidated. Here, I first review related mechanisms of brain ischemia and then data evaluating the neuroprotective effects of HO in focal and global ischemic animal models. I clearly establish that the cerebrovascular, extracellular matrix, plasma membrane, endoplasmic reticulum, mitochondrial, and lysosomal reactions are critical in neuroprotection induced by HO in focal ischemia. In rats and mice, the middle cerebral artery occlusion (MCAO) model was used to represent cerebrovascular stroke. Neuroprotection induced by HO exhibits specific adaptation responses that involve a number of cellular and biochemical alterations, including metabolic homeostasis and reprogramming of gene expression. The changes in the metabolic pathways are generally short lived and reversible, while the consequences of gene expression are a long-term process and may lead to the permanent alteration in the pattern of gene expression. The neuroprotection provided by HO may have important clinical implications. Therefore, it is important to assess the benefits and risks of HO therapy in noninfarcted tissue

Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications.

Trop2 is a transmembrane glycoprotein encoded by the Tacstd2 gene. It is an intracellular calcium signal transducer that is differentially expressed in many cancers. It signals cells for self-renewal, proliferation, invasion, and survival. It has stem cell-like qualities. Trop2 is expressed in many normal tissues, though in contrast, it is overexpressed in many cancers and the overexpression of Trop2 is of prognostic significance. Several ligands have been proposed that interact with Trop2. Trop2 signals the cells via different pathways and it is transcriptionally regulated by a complex network of several transcription factors. Trop2 expression in cancer cells has been correlated with drug resistance. Several strategies target Trop2 on cancer cells that include antibodies, antibody fusion proteins, chemical inhibitors, nanoparticles, etc. The in vitro studies and pre-clinical studies, using these various therapeutic treatments, have resulted in significant inhibition of tumor cell growth both in vitro and in vivo in mice. A clinical study is underway using IMMU-132 (hrS7 linked to SN38) in patients with epithelial cancers. This review describes briefly the various characteristics of cancer cells overexpressing Trop2 and the potential application of Trop2 as both a prognostic biomarker and as a therapeutic target to reverse resistance

Radiation-induced neuroinflammation:a potential protective role for poly(ADP-ribose) polymerase inhibitors?

Radiotherapy (RT) plays a fundamental role in the treatment of glioblastoma (GBM). GBM are notoriously invasive and harbor a subpopulation of cells with stem-like features which exhibit upregulation of the DNA damage response (DDR) and are radioresistant. High radiation doses are therefore delivered to large brain volumes and are known to extend survival but also cause delayed toxicity with 50%–90% of patients developing neurocognitive dysfunction. Emerging evidence identifies neuroinflammation as a critical mediator of the adverse effects of RT on cognitive function. In addition to its well-established role in promoting repair of radiation-induced DNA damage, activation of poly(ADP-ribose) polymerase (PARP) can exacerbate neuroinflammation by promoting secretion of inflammatory mediators. Therefore, PARP represents an intriguing mechanistic link between radiation-induced activation of the DDR and subsequent neuroinflammation. PARP inhibitors (PARPi) have emerged as promising new agents for GBM when given in combination with RT, with multiple preclinical studies demonstrating radiosensitizing effects and at least 3 compounds being evaluated in clinical trials. We propose that concomitant use of PARPi could reduce radiation-induced neuroinflammation and reduce the severity of radiation-induced cognitive dysfunction while at the same time improving tumor control by enhancing radiosensitivity

Role of biomechanical forces in the natural history of coronary atherosclerosis.

Atherosclerosis remains a major cause of morbidity and mortality worldwide, and a thorough understanding of the underlying pathophysiological mechanisms is crucial for the development of new therapeutic strategies. Although atherosclerosis is a systemic inflammatory disease, coronary atherosclerotic plaques are not uniformly distributed in the vascular tree. Experimental and clinical data highlight that biomechanical forces, including wall shear stress (WSS) and plaque structural stress (PSS), have an important role in the natural history of coronary atherosclerosis. Endothelial cell function is heavily influenced by changes in WSS, and longitudinal animal and human studies have shown that coronary regions with low WSS undergo increased plaque growth compared with high WSS regions. Local alterations in WSS might also promote transformation of stable to unstable plaque subtypes. Plaque rupture is determined by the balance between PSS and material strength, with plaque composition having a profound effect on PSS. Prospective clinical studies are required to ascertain whether integrating mechanical parameters with medical imaging can improve our ability to identify patients at highest risk of rapid disease progression or sudden cardiac events.This work was supported by the British Heart Foundation (FS/13/33/30168), Heart Research UK (RG2638/14/16), the Cambridge NIHR Biomedical Research Centre, and the BHF Cambridge Centre for Research Excellence.This is the author accepted manuscript. The final version is available from Nature Publishing Group at http://dx.doi.org/10.1038/nrcardio.2015.203