Endothelial cells transduce the frictional force from blood flow (fluid shear stress) into biochemical signals that regulate gene expression and cell behavior via specialized mechanisms and pathways. ...These pathways shape the vascular system during development and during postnatal and adult life to optimize flow to tissues. The same pathways also contribute to atherosclerosis and vascular malformations. This Review covers recent advances in basic mechanisms of flow signaling and the involvement of these mechanisms in vascular physiology, remodeling, and these diseases. We propose that flow sensing pathways that govern normal morphogenesis can contribute to disease under pathological conditions or can be altered to induce disease. Viewing atherosclerosis and vascular malformations as instances of pathological morphogenesis provides a unifying perspective that may aid in developing new therapies.
Direct recognition of invading pathogens by innate immune cells is a critical driver of the inflammatory response. However, cells of the innate immune system can also sense their local ...microenvironment and respond to physiological fluctuations in temperature, pH, oxygen and nutrient availability, which are altered during inflammation. Although cells of the immune system experience force and pressure throughout their life cycle, little is known about how these mechanical processes regulate the immune response. Here we show that cyclical hydrostatic pressure, similar to that experienced by immune cells in the lung, initiates an inflammatory response via the mechanically activated ion channel PIEZO1. Mice lacking PIEZO1 in innate immune cells showed ablated pulmonary inflammation in the context of bacterial infection or fibrotic autoinflammation. Our results reveal an environmental sensory axis that stimulates innate immune cells to mount an inflammatory response, and demonstrate a physiological role for PIEZO1 and mechanosensation in immunity.
Endothelial responses to fluid shear stress are essential for vascular development and physiology, and determine the formation of atherosclerotic plaques at regions of disturbed flow. Previous work ...identified VE-cadherin as an essential component, along with PECAM-1 and VEGFR2, of a complex that mediates flow signaling. However, VE-cadherin's precise role is poorly understood. We now show that the transmembrane domain of VE-cadherin mediates an essential adapter function by binding directly to the transmembrane domain of VEGFR2, as well as VEGFR3, which we now identify as another component of the junctional mechanosensory complex. VEGFR2 and VEGFR3 signal redundantly downstream of VE-cadherin. Furthermore, VEGFR3 expression is observed in the aortic endothelium, where it contributes to flow responses in vivo. In summary, this study identifies a novel adapter function for VE-cadherin mediated by transmembrane domain association with VEGFRs.
The physiological functions of endothelial cells control vascular tone, permeability, inflammation, and angiogenesis, which significantly help to maintain a healthy vascular system. Several ...cardiovascular diseases are characterized by endothelial cell activation or dysfunction triggered by external stimuli such as disturbed flow, hypoxia, growth factors, and cytokines in response to high levels of low-density lipoprotein and cholesterol, hypertension, diabetes, aging, drugs, and smoking. Increasing evidence suggests that uncontrolled proinflammatory signaling and further alteration in endothelial cell phenotypes such as barrier disruption, increased permeability, endothelial to mesenchymal transition (EndMT), and metabolic reprogramming further induce vascular diseases, and multiple studies are focusing on finding the pathways and mechanisms involved in it. This review highlights the main proinflammatory stimuli and their effects on endothelial cell function. In order to provide a rational direction for future research, we also compiled the most recent data regarding the impact of endothelial cell dysfunction on vascular diseases and potential targets that impede the pathogenic process.
Blood vessels permit the selective passage of molecules and immune cells between tissues and circulation. Uncontrolled inflammatory responses from an infection can increase vascular permeability and ...edema, which can occasionally lead to fatal organ failure. We identified mexenone as a vascular permeability blocker by testing 2,910 compounds in the Clinically Applied Compound Library using the lipopolysaccharide (LPS)-induced vascular permeability assay. Mexenone suppressed the LPS-induced downregulation of junctional proteins and phosphorylation of VE-cadherin in Bovine Aortic Endothelial Cells (BAECs). The injection of mexenone 1 hr before LPS administration completely blocked LPS-induced lung vascular permeability and acute lung injury in mice after 18hr. Our results suggest that mexenone-induced endothelial cell (EC) barrier stabilization could be effective in treating sepsis patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
7.
Multiple roles of phosphoinositide-specific phospholipase C isozymes Suh, P.G. (Pohang University of Science and Technology, Pohang, Republic of Korea), E-mail: pgs@postech.ac.kr; Park, J.I. (Pohang University of Science and Technology, Pohang, Republic of Korea); Manzoli, Lucia (University of Bologna, Bologna, Italy) ...
BMB reports,
06/2008, Letnik:
41, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Phosphoinositide-specific phospholipase C is an effector molecule in the signal transduction process. It generates two second messengers, inositol-1,4,5-trisphosphate and diacylglycerol from ...phosphatidylinositol 4,5-bisphosphate. Currently, thirteen mammal PLC isozymes have been identified, and they are divided into six groups: PLC-β, -γ, -δ, -ε, -ζ and -η. Sequence analysis studies demonstrated that each isozyme has more than one alternative splicing variant. PLC isozymes contain the X and Y domains that are responsible for catalytic activity. Several other domains including the PH domain, the C2 domain and EF hand motifs are involved in various biological functions of PLC isozymes as signaling proteins. The distribution of PLC isozymes is tissue and organ specific. Recent studies on isolated cells and knockout mice depleted of PLC isozymes have revealed their distinct phenotypes. Given the specificity in distribution and cellular localization, it is clear that each PLC isozyme bears a unique function in the modulation of physiological responses. In this review, we discuss the structural organization, enzymatic properties and molecular diversity of PLC splicing variants and study functional and physiological roles of each isozyme.
Background
Fibronectin in endothelial basement membranes promotes endothelial inflammatory activation and atherosclerosis but also promotes plaque stability and vascular remodeling. The fibronectin ...receptor α5 subunit is proinflammatory through binding to and activating phosphodiesterase 4D5, which inhibits anti‐inflammatory cyclic adenosine monophosphate and protein kinase A. Replacing the α5 cytoplasmic domain with that of α2 resulted in smaller atherosclerotic plaques. Here, we further assessed plaque phenotype and compensatory vascular remodeling in this model.
Methods and Results
α5/2 mice in the hyperlipidemic apolipoprotein E null background had smaller plaques in the aortic root, with reduced endothelial NF‐κB activation and inflammatory gene expression, reduced leukocyte content, and much lower metalloproteinase expression. However, smooth muscle cell content, fibrous cap thickness, and fibrillar collagen were unchanged, indicating no shift toward vulnerability. In vivo knockdown of phosphodiesterase 4D5 also decreased endothelial inflammatory activation and atherosclerotic plaque size. α5/2 mice showed improved recovery from hindlimb ischemia after femoral artery ligation.
Conclusions
Blocking the fibronectin‐Integrin α5 pathway reduces atherosclerotic plaque size, maintains plaque stability, and improves compensatory remodeling. This pathway is therefore a potential therapeutic target for treatment of atherosclerosis.
Integrins in mechanotransduction Ross, Tyler D; Coon, Brian G; Yun, Sanguk ...
Current opinion in cell biology,
10/2013, Letnik:
25, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Forces acting on cells govern many important regulatory events during development, normal physiology, and disease processes. Integrin-mediated adhesions, which transmit forces between the ...extracellular matrix and the actin cytoskeleton, play a central role in transducing effects of forces to regulate cell functions. Recent work has led to major insights into the molecular mechanisms by which these adhesions respond to forces to control cellular signaling pathways. We briefly summarize effects of forces on organs, tissues, and cells; and then discuss recent advances toward understanding molecular mechanisms.
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