Impairment of microvascular endothelial Kir2.1 channels contributes to endothelial dysfunction in human hypertension.

Hypertension is associated with decreased endothelial function through reduced contributions of nitric oxide (NO). We previously discovered that flow-induced NO production in resistance arteries of mice and humans critically depends on endothelial inwardly rectifying K (Kir2.1) channels.

3D printing with a 3D printed digital material filament for programming functional gradients.

Additive manufacturing, or 3D printing attracts growing attention as a promising method for creating functionally graded materials. Fused deposition modeling (FDM) is widely available, but due to its simple process, creating spatial gradation of diverse properties using FDM is challenging. Here, we present a 3D printed digital material filament that is structured towards 3D printing of functional gradients, utilizing only a readily available FDM printer and filaments.

Erratum: Piezo1 induces endothelial responses to shear stress via soluble adenylyl Cyclase-IPR2 circuit.

[This corrects the article DOI: 10.1016/j.isci.

Piezo1 induces endothelial responses to shear stress via soluble adenylyl Cyclase-IPR2 circuit.

Endothelial cells (ECs) continuously sense and adapt to changes in shear stress generated by blood flow. Here, we show that the activation of the mechanosensitive channel Piezo1 by defined shear forces induces Ca entry into the endoplasmic reticulum (ER) via the ER Ca ATPase pump. This entry is followed by inositol trisphosphate receptor 2 (IPR2)-elicited ER Ca release into the cytosol.

Impairment of endothelial glycocalyx in atherosclerosis and obesity.

Endothelial glycocalyx is a negatively charged gel-like layer located on the apical surface of endothelial cells. It serves as a selective two-way physical barrier between the flowing blood and the endothelium, which regulates the access of macromolecules and of blood cells to the endothelial surface. In addition, endothelial glycocalyx plays a major role in sensing mechanical signals generated by the blood flow and transducing these signals to maintain endothelial functions; Thus, dysfunction or disruption of endothelial glycocalyx in pathological condition leads to endothelial dysfunction and contributes to the development of vascular diseases.

Caveolin-1 is a primary determinant of endothelial stiffening associated with dyslipidemia, disturbed flow, and ageing.

Endothelial stiffness is emerging as a major determinant in endothelial function. Here, we analyzed the role of caveolin-1 (Cav-1) in determining the stiffness of endothelial cells (EC) exposed to oxidized low density lipoprotein (oxLDL) under static and hemodynamic conditions in vitro and of aortic endothelium in vivo in mouse models of dyslipidemia and ageing. Elastic moduli of cultured ECs and of the endothelial monolayer of freshly isolated mouse aortas were measured using atomic force microscopy (AFM).

Isolation and Identification of Vascular Endothelial Cells from Distinct Adipose Depots for Downstream Applications.

Vascular endothelial cells lining the wall of the vascular system play important roles in a variety of physiological processes, including vascular tone regulation, barrier functions, and angiogenesis. Endothelial cell dysfunction is a hallmark predictor and major driver for the progression of severe cardiovascular diseases, yet the underlying mechanisms remain poorly understood. The ability to isolate and perform analyses on endothelial cells from various vascular beds in their native form will give insight into the processes of cardiovascular disease.

Cholesterol-induced suppression of Kir2 channels is mediated by decoupling at the inter-subunit interfaces.

Cholesterol is a major regulator of multiple types of ion channels. Although there is increasing information about cholesterol binding sites, the molecular mechanisms through which cholesterol binding alters channel function are virtually unknown. In this study, we used a combination of Martini coarse-grained simulations, a network theory-based analysis, and electrophysiology to determine the effect of cholesterol on the dynamic structure of the Kir2.

Differential effects of obesity on visceral versus subcutaneous adipose arteries: role of shear-activated Kir2.1 and alterations to the glycocalyx.

Obesity imposes well-established deficits to endothelial function. We recently showed that obesity-induced endothelial dysfunction was mediated by disruption of the glycocalyx and a loss of Kir channel flow sensitivity. However, obesity-induced endothelial dysfunction is not observed in all vascular beds: visceral adipose arteries (VAAs), but not subcutaneous adipose arteries (SAAs), exhibit endothelial dysfunction.

Cholesterol-Induced Suppression of Endothelial Kir Channels Is a Driver of Impairment of Arteriolar Flow-Induced Vasodilation in Humans.

Dyslipidemia-induced endothelial dysfunction is an important factor in the progression of cardiovascular disease; however, the underlying mechanisms are unclear. Our recent studies demonstrated that flow-induced vasodilation (FIV) is regulated by inwardly rectifying K channels (Kir2.1) in resistance arteries.

Integrin-based mechanosensing through conformational deformation.

Conversion of integrins from low to high affinity states, termed activation, is important in biological processes, including immunity, hemostasis, angiogenesis, and embryonic development. Integrin activation is regulated by large-scale conformational transitions from closed, low affinity states to open, high affinity states. Although it has been suggested that substrate stiffness shifts the conformational equilibrium of integrin and governs its unbinding, here, we address the role of integrin conformational activation in cellular mechanosensing.

Actin flow-dependent and -independent force transmission through integrins.

Integrin-dependent adhesions mediate reciprocal exchange of force and information between the cell and the extracellular matrix. These effects are attributed to the "focal adhesion clutch," in which moving actin filaments transmit force to integrins via dynamic protein interactions. To elucidate these processes, we measured force on talin together with actin flow speed.

The Pta-AckA Pathway Regulates LrgAB-Mediated Pyruvate Uptake in .

Pyruvate forms the central node of carbon metabolism and promotes growth as an alternative carbon source during starvation. We recently revealed that LrgAB functions as a stationary phase pyruvate uptake system in the primary causative agent of human dental caries, but its underlying regulatory mechanisms are still not clearly understood. This study was aimed at further characterizing the regulation of LrgAB from a metabolomic perspective.

Regulation of cid and lrg expression by CodY in Streptococcus mutans.

The ability of Streptococcus mutans to persist in a variety of adverse environments and to emerge as a numerically dominant member of stable oral biofilm communities are essential elements for its cariogenicity. The S. mutans Cid/Lrg system has been studied as a key player in the integration of complex environmental signals into regulatory networks that modulate virulence and cell homeostasis.

Acetate and Potassium Modulate the Stationary-Phase Activation of in .

Fluctuating environments force bacteria to constantly adapt and optimize the uptake of substrates to maintain cellular and nutritional homeostasis. Our recent findings revealed that LrgAB functions as a pyruvate uptake system in , and its activity is modulated in response to glucose and oxygen levels. Here, we show that the composition of the growth medium dramatically influences the magnitude and pattern of activation.

Environmental Triggers of Expression in .

The and operons of encode proteins that are structurally similar to the bacteriophage lambda family of holin-antiholin proteins, which are believed to facilitate cell death in other bacterial species. Although their precise function is not known, and are linked to multiple virulence traits of , including oxidative stress tolerance, biofilm formation, and autolysis. Here we investigate the regulation of which in shows a complex dependence on growth conditions that is not fully understood.

Peptides encoded in the RcrRPQ operon are essential for thermotolerance.

The MarR-like transcriptional regulator and two ABC transporters encoded by the operon in the dental caries pathogen have important regulatory roles related to oxidative stress tolerance, genetic competence and (p)ppGpp metabolism. A unique feature of the operon, when compared to other bacteria, is the presence of two peptides, designated Pep1 and Pep2, encoded in alternative reading frames at the 3' end of . Here, we show that the operon, including Pep1 and 2, is essential for to survive and maintain viability at elevated temperatures.

Mechanisms of endothelial stiffening in dyslipidemia and aging: Oxidized lipids and shear stress.

Vascular stiffening of the arterial walls is well-known as a key factor in aging and the development of cardiovascular disease; however, the role of endothelial stiffness in vascular dysfunction is still an emerging topic. In this review, the authors discuss the impact of dyslipidemia, oxidized lipids, substrate stiffness, age and pro-atherogenic disturbed flow have on endothelial stiffness. Furthermore, we investigate several mechanistic pathways that are key contributors in endothelial stiffness and discuss their physiological effects in the onset of atherogenesis in the disturbed flow regions of the aortic vasculature.

MicroRNA-dependent regulation of biomechanical genes establishes tissue stiffness homeostasis.

Vertebrate tissues exhibit mechanical homeostasis, showing stable stiffness and tension over time and recovery after changes in mechanical stress. However, the regulatory pathways that mediate these effects are unknown. A comprehensive identification of Argonaute 2-associated microRNAs and mRNAs in endothelial cells identified a network of 122 microRNA families that target 73 mRNAs encoding cytoskeletal, contractile, adhesive and extracellular matrix (CAM) proteins.