Permissive role of vascular endothelium in fibrosis: focus on the kidney.

Fibrosis, the morphologic end-result of a plethora of chronic conditions and the scorch for organ function, has been thoroughly investigated. One aspect of its development and progression, namely the permissive role of vascular endothelium, has been overshadowed by studies into (myo)fibroblasts and TGF-β; thus, it is the subject of the present review. It has been established that tensile forces of the extracellular matrix acting on cells are a prerequisite for mechanochemical coupling, leading to liberation of TGF-β and formation of myofibroblasts.

Glomerular microcirculation: Implications for diabetes, preeclampsia, and kidney injury.

This review outlines the features of tandem regulation of glomerular microcirculation by autoregulatory mechanisms and intraglomerular redistribution of blood flow. Multiple points of cooperation exist between autoregulatory and distributional mechanisms. Mutual interactions between myogenic and tubuloglomerular feedback (TGF) mechanisms regulating the inflow are briefly discussed.

Endothelial Glycocalyx and Cardiomyocyte Damage Is Prevented by Recombinant Syndecan-1 in Acute Myocardial Infarction.

The outer layer of endothelial cells (ECs), consisting of the endothelial glycocalyx (eGC) and the cortex (CTX), provides a protective barrier against vascular diseases. Structural and functional impairments of their mechanical properties are recognized as hallmarks of endothelial dysfunction and can lead to cardiovascular events, such as acute myocardial infarction (AMI). This study investigated the effects of AMI on endothelial nanomechanics and function and the use of exogenous recombinant syndecan-1 (rSyn-1), a major component of the eGC, as recovering agent.

Emerging Insights into Glomerular Vascular Pole and Microcirculation.

The glomerular vascular pole is the gate for the afferent and efferent arterioles and mesangial cells and a frequent location of peripolar cells with an unclear function. It has been studied in definitive detail for >30 years, and functionally interrogated in the context of signal transduction from the macula densa to the mesangial cells and afferent arteriolar smooth muscle cells from 10 to 20 years ago. Two recent discoveries shed additional light on the vascular pole, with possibly far-reaching implications.

Oscillators in the microvasculature: glycocalyx and beyond.

The growing recognition of abundance of oscillating functions in biological systems has motivated this brief overview, which narrows down on the microvasculature. Specifically, it encompasses self-sustained oscillations of blood flow, hematocrit, and viscosity at bifurcations; blood flow effects on the oscillations of endothelial glycocalyx, mechanotransduction, and its termination to prime endothelial cells for the subsequent mechanical signaling event; oscillating affinity of hyaluronan-CD44 binding domain; spontaneous contractility of actomyosin complexes in the cortical actin web and its effects on the tension of the plasma membrane; reversible effects of sirtuin-1 on endothelial glycocalyx; and effects of plasma membrane tension on endo- and exocytosis. Some potential interactions between those oscillators, and their coupling, are discussed together with their transition into chaotic movements.

Ways and Means of Cellular Reconditioning for Kidney Regeneration.

Background: Mitochondrial, lysosomal, and peroxisomal dysfunction; defective autophagy; mitophagy; and pexophagy, as well as the loss of glycocalyx integrity are known contributors to initiation and progression of diverse kidney diseases. Those cellular organelles are tightly interactive in health, and during development of a disease, damage in one may propagate to others. By extension, it follows that restoring an individual defect may culminate in a broader restorative spectrum and improvement of cell and organ functions.

Biomechanical properties of endothelial glycocalyx: An imperfect pendulum.

Endothelial glycocalyx plays a crucial role in hemodynamics in health and disease, yet studying it is met by multiple technical hindrances. We attempted to outline our views on some biomechanical properties of endothelial glycocalyx, which are potentially amenable to mathematical modeling. We start with the null-hypothesis ascribing to glycocalyx the properties of a pendulum and reject this hypothesis on the grounds of multiple obstacles for pendulum behavior, such as rich decoration with flexible negatively charged side-chains, variable length and density, fluid fixation to the plasma membrane.

Cross talk between endothelial and red blood cell glycocalyces via near-field flow.

Vascular endothelial cells and circulating red blood cell (RBC) surfaces are both covered by a layer of bushy glycocalyx. The interplay between these glycocalyx layers is hardly measurable and insufficiently understood. This study aims to investigate and qualify the possible interactions between the glycocalyces of RBCs and endothelial cells using mathematical modeling and numerical simulation.

Sirtuin 1 and endothelial glycocalyx.

Sirtuin1 deficiency or reduced activity comprises one of the hallmarks of diseases as diverse as chronic cardiovascular, renal, and metabolic, some malignancies, and infections, as well as aging-associated diseases. In a mouse model of endothelium-limited defect in sirtuin 1 deacetylase activity, we found a dramatic reduction in the volume of endothelial glycocalyx. This was associated with the surge in the levels of one of key scaffolding heparan sulfate proteoglycans of endothelial glycocalyx, syndecan-4, and specifically, its extracellular domain (ectodomain).

Chronic Kidney Disease: A Vicarious Relation to Premature Cell Senescence.

Chronic kidney disease (CKD), commonly fostering nonrenal complications, themselves more life threatening than renal pathology, remains enigmatic. Despite more than a century of intense research, therapeutic options to halt or reverse renal disease are rather limited. Recently, similarity between manifestations of progressive CKD and aging kidney has attracted investigative attention that revealed senescent cells and secreting proinflammatory and profibrotic mediators in all renal compartments, even at young age, in patients with kidney maladies.

The Cell "Coat of Many Colors".

This Guest Editorial introduces the theme reviews focusing on the glycocalyx in human disease.

Glycocalyx in Endotoxemia and Sepsis.

Along with the recognition of a crucial role played by endothelial dysfunction secondarily igniting cardiovascular, pulmonary, and renal complications, investigational focus has extended toward endothelial glycocalyx. This delicate coating of cells, including the vascular endothelium, regulates permeability, leukocyte traffic, nitric oxide production, and coagulation, and harbors diverse growth and survival factors. In this brief overview, we discuss the metabolic signatures of sepsis as they relate to the loss of glycocalyx integrity and highlight the contribution of several proteases, heparanase, and hyaluronidase to the shedding of glycocalyx.

Fibrogenic Secretome of Sirtuin 1-Deficient Endothelial Cells: Wnt, Notch and Glycocalyx Rheostat.

Sirtuins (SIRT) are ubiquitous histone and protein deacetylases and a member of this family, SIRT1, is the best-studied one. Its functions in endothelial cells encompass branching angiogenesis, activation of endothelial nitric oxide synthase, regulation of proapoptotic and proinflammatory pathways, among others. Defective SIRT1 activity has been described in various cardiovascular, renal diseases and in aging-associated conditions.

Dickkopf-3 in aberrant endothelial secretome triggers renal fibroblast activation and endothelial-mesenchymal transition.

Background: Our laboratory has previously demonstrated that Sirt1endo-/- mice show endothelial dysfunction and exaggerated renal fibrosis, whereas mice with silenced endothelial transforming growth factor beta (TGF-β) signaling are resistant to fibrogenic signals. Considering the fact that the only difference between these mutant mice is confined to the vascular endothelium, this indicates that secreted substances contribute to these contrasting responses.

Methods: We performed an unbiased proteomic analysis of the secretome of renal microvascular endothelial cells (RMVECs) isolated from these two mutants.

Perioperative implication of the endothelial glycocalyx.

The endothelial glycocalyx (EG) is a gel-like layer lining the luminal surface of healthy vascular endothelium. Recently, the EG has gained extensive interest as a crucial regulator of endothelial funtction, including vascular permeability, mechanotransduction, and the interaction between endothelial and circulating blood cells. The EG is degraded by various enzymes and reactive oxygen species upon pro-inflammatory stimulus.

Endothelial cell dysfunction and glycocalyx - A vicious circle.

Dysfunctional endothelial cells are an essential contributor to the progression of diverse chronic cardiovascular, renal, and metabolic diseases. It manifests in impairment of nitric oxide-dependent vasorelaxation, vascular permeability, and leukocytes deterrent. While endothelial glycocalyx is known to regulate these functions, glycocalyx has been shown to be impaired in pathologic settings leading to endothelial dysfunction.

Endothelial dysfunction is a superinducer of syndecan-4: fibrogenic role of its ectodomain.

Syndecan-4 (Synd4) is a member of the membrane-spanning, glycocalyx-forming proteoglycan family. It has been suggested that Synd4 participates in renal fibrosis. We compared wild-type and fibrosis-prone endothelial sirtuin 1-deficient (Sirt1) mice, the latter being a model of global endothelial dysfunction.

Endothelial glycocalyx-the battleground for complications of sepsis and kidney injury.

After briefly discussing endothelial glycocalyx and its role in vascular physiology and renal disease, this overview focuses on its degradation very early in the course of microbial sepsis. We describe our recently proposed mechanism for glycocalyx degradation induced by exocytosis of lysosome-related organelles and release of their cargo. Notably, an intermediate in nitric oxide synthesis, NG-hydroxy-l-arginine, shows efficacy in curtailing exocytosis of these organelles and improvement in animal survival.

The third path of tubulointerstitial fibrosis: aberrant endothelial secretome.

The secretome, defined as a portion of proteins secreted by specific cells to the extracellular space, secures a proper microenvironmental niche not only for the donor cells, but also for the neighboring cells, thus maintaining tissue homeostasis. Communication via secretory products exists between endothelial cells and fibroblasts, and this local mechanism maintains the viability and density of each compartment. Endothelial dysfunction, apart from obvious cell-autonomous defects, leads to the aberrant secretome, which predisposes fibroblasts to acquire a myofibroblastic fibrogenic phenotype.

Instructive Role of the Microenvironment in Preventing Renal Fibrosis.

Accumulation of myofibroblasts is a hallmark of renal fibrosis. A significant proportion of myofibroblasts has been reported to originate via endothelial-mesenchymal transition. We initially hypothesized that exposing myofibroblasts to the extract of endothelial progenitor cells (EPCs) could reverse this transition.

Vascular endothelium in diabetes.

Three decades ago a revolutionary idea was born that ascribed to dysfunctional endothelia some manifestations of diabetes, the Steno hypothesis, so named after the Steno Diabetes Center, Gentofte, in Denmark. Here I briefly outline the accomplishments accrued in the past 15 years to buttress this hypothesis. Those include development of novel technological platforms to examine microcirculatory beds, deeper understanding of patterns of microvascular derangement in diabetes, pathophysiology of nitric oxide synthesis and availability, nitrosative and oxidative stress in diabetes, premature senescence of endothelial cells and the role of sirtuin 1 and lysosomal dysfunction in this process, and the state of endothelial glycocalyx and endothelial progenitor cells in diabetes.

Mechanotransduction of the endothelial glycocalyx mediates nitric oxide production through activation of TRP channels.

The endothelial surface glycocalyx (ESG) is a carbohydrate-rich layer found on the vascular endothelium, serving critical functions in the mechanotransduction of blood flow-induced forces. One of the most important protective functions of the ESG is to mediate the production of nitric oxide (NO) in response to blood flow. However, the detailed mechanism underlying ESG's mechanotransduction of the production of NO has not been completely identified.

Endothelial sirtuin 1 inactivation enhances capillary rarefaction and fibrosis following kidney injury through Notch activation.

Peritubular capillary (PTC) rarefaction along with tissue fibrosis is a hallmark of chronic kidney disease (CKD). However, molecular mechanisms of PTC loss have been poorly understood. Previous studies have demonstrated that functional loss of endothelial sirtuin 1 (SIRT1) impairs angiogenesis during development and tissue damage.