Multi-scale interaction of flow and the artery wall

We discuss, from the perspective of basic science, the physical and biological processes which underlie atherosclerotic (plaque) initiation at the vascular endothelium, identifying their widely separated spatial and temporal scales which participate. We draw on current, related models of vessel wall evolution, paying particular attention to the role of flow, and proceed to propose, then validate (in practical, qualitative terms, at least) a multiply coupled, multi-scale modeling strategy, which, eventually, aims at a quantitative, patient-specific understanding of the coupling between the flow and the endothelial state

TNF-mediated damage to glomerular endothelium is an important determinant of acute kidney injury in sepsis

Severe sepsis is often accompanied by acute kidney injury (AKI) and albuminuria. Here we studied whether the AKI and albuminuria associated with lipopolysaccharide (LPS) treatment in mice reflects impairment of the glomerular endothelium with its associated endothelial surface layer. LPS treatment decreased the abundance of endothelial surface layer heparan sulfate proteoglycans and sialic acid, and led to albuminuria likely reflecting altered glomerular filtration perm-selectivity. LPS treatment decreased the glomerular filtration rate (GFR), while also causing significant ultrastructural alterations in the glomerular endothelium. The density of glomerular endothelial cell fenestrae was 5-fold lower whereas the average fenestrae diameter was 3-fold higher in LPS-treated than in control mice. The effects of LPS on the glomerular endothelial surface layer, endothelial cell fenestrae, GFR, and albuminuria were diminished in TNF receptor 1 (TNFR1) knockout mice, suggesting that these LPS effects are mediated by TNF-α activation of TNFR1. Indeed, intravenous administration of TNF decreased GFR and led to loss of glomerular endothelial cell fenestrae, increased fenestrae diameter, and damage to the glomerular endothelial surface layer. LPS treatment decreased kidney expression of vascular endothelial growth factor (VEGF). Thus, our findings confirm the important role of glomerular endothelial injury, possibly by a decreased VEGF level, in the development and progression of AKI and albuminuria in the LPS model of sepsis in the mouse

Evaluation of the Glomerular Filtration Barrier by Electron Microscopy

The plasma filtration and formation of the urine is a very complex process necessary for the elimination of metabolites, toxins, and excessive water and electrolytes from the body. The initial process of urine formations is done by the glomerular filtration barrier inside the glomeruli. This specialized barrier consists of three layers, fenestrated endothelium, basement membrane, and podocytes, which ensure that water and small molecules pass through while cells and large molecules are retained. The glomerular filtration barrier is found with abnormal morphology in several diseases and is associated with renal malfunction; thus, it is interesting to study these structures in different experimental and clinical conditions. The normal glomerular barrier and its alterations in some conditions (hypertension, diabetes, and fetal programming) are discussed in this chapter. Furthermore, some methods for studying the glomerular filtration barrier by electron microscopy, both by qualitative and quantitative methods, are present

What is the mechanism of microalbuminuria in diabetes: a role for the glomerular endothelium?

Microalbuminuria is an important risk factor for cardiovascular disease and progressive renal impairment. This holds true in the general population and particularly in those with diabetes, in whom it is common and marks out those likely to develop macrovascular disease and progressive renal impairment. Understanding the pathophysiological mechanisms through which microalbuminuria occurs holds the key to designing therapies to arrest its development and prevent these later manifestations

Physiologic upper limits of pore size of different blood capillary types and another perspective on the dual pore theory of microvascular permeability

<p>Abstract</p> <p>Background</p> <p>Much of our current understanding of microvascular permeability is based on the findings of classic experimental studies of blood capillary permeability to various-sized lipid-insoluble endogenous and non-endogenous macromolecules. According to the classic small pore theory of microvascular permeability, which was formulated on the basis of the findings of studies on the transcapillary flow rates of various-sized systemically or regionally perfused endogenous macromolecules, transcapillary exchange across the capillary wall takes place through a single population of small pores that are approximately 6 nm in diameter; whereas, according to the dual pore theory of microvascular permeability, which was formulated on the basis of the findings of studies on the accumulation of various-sized systemically or regionally perfused non-endogenous macromolecules in the locoregional tissue lymphatic drainages, transcapillary exchange across the capillary wall also takes place through a separate population of large pores, or capillary leaks, that are between 24 and 60 nm in diameter. The classification of blood capillary types on the basis of differences in the physiologic upper limits of pore size to transvascular flow highlights the differences in the transcapillary exchange routes for the transvascular transport of endogenous and non-endogenous macromolecules across the capillary walls of different blood capillary types.</p> <p>Methods</p> <p>The findings and published data of studies on capillary wall ultrastructure and capillary microvascular permeability to lipid-insoluble endogenous and non-endogenous molecules from the 1950s to date were reviewed. In this study, the blood capillary types in different tissues and organs were classified on the basis of the physiologic upper limits of pore size to the transvascular flow of lipid-insoluble molecules. Blood capillaries were classified as non-sinusoidal or sinusoidal on the basis of capillary wall basement membrane layer continuity or lack thereof. Non-sinusoidal blood capillaries were further sub-classified as non-fenestrated or fenestrated based on the absence or presence of endothelial cells with fenestrations. The sinusoidal blood capillaries of the liver, myeloid (red) bone marrow, and spleen were sub-classified as reticuloendothelial or non-reticuloendothelial based on the phago-endocytic capacity of the endothelial cells.</p> <p>Results</p> <p>The physiologic upper limit of pore size for transvascular flow across capillary walls of non-sinusoidal non-fenestrated blood capillaries is less than 1 nm for those with interendothelial cell clefts lined with zona occludens junctions (i.e. brain and spinal cord), and approximately 5 nm for those with clefts lined with macula occludens junctions (i.e. skeletal muscle). The physiologic upper limit of pore size for transvascular flow across the capillary walls of non-sinusoidal fenestrated blood capillaries with diaphragmed fenestrae ranges between 6 and 12 nm (i.e. exocrine and endocrine glands); whereas, the physiologic upper limit of pore size for transvascular flow across the capillary walls of non-sinusoidal fenestrated capillaries with open 'non-diaphragmed' fenestrae is approximately 15 nm (kidney glomerulus). In the case of the sinusoidal reticuloendothelial blood capillaries of myeloid bone marrow, the transvascular transport of non-endogenous macromolecules larger than 5 nm into the bone marrow interstitial space takes place via reticuloendothelial cell-mediated phago-endocytosis and transvascular release, which is the case for systemic bone marrow imaging agents as large as 60 nm in diameter.</p> <p>Conclusions</p> <p>The physiologic upper limit of pore size in the capillary walls of most non-sinusoidal blood capillaries to the transcapillary passage of lipid-insoluble endogenous and non-endogenous macromolecules ranges between 5 and 12 nm. Therefore, macromolecules larger than the physiologic upper limits of pore size in the non-sinusoidal blood capillary types generally do not accumulate within the respective tissue interstitial spaces and their lymphatic drainages. In the case of reticuloendothelial sinusoidal blood capillaries of myeloid bone marrow, however, non-endogenous macromolecules as large as 60 nm in diameter can distribute into the bone marrow interstitial space via the phago-endocytic route, and then subsequently accumulate in the locoregional lymphatic drainages of tissues following absorption into the lymphatic drainage of periosteal fibrous tissues, which is the lymphatic drainage of myeloid bone marrow. When the ultrastructural basis for transcapillary exchange across the capillary walls of different capillary types is viewed in this light, it becomes evident that the physiologic evidence for the existence of aqueous large pores ranging between 24 and 60 nm in diameter in the capillary walls of blood capillaries, is circumstantial, at best.</p

Large-scale molecular dynamics simulation of coupled dynamics of flow and glycocalyx: towards understanding atomic events on an endothelial cell surface

The glycocalyx has a prominent role in orchestrating multiple biological processes occurring at the plasma membrane. In this paper, an all-atom flow/glycocalyx system is constructed with the bulk flow velocity in the physiologically relevant ranges for the first time. The system is simulated by molecular dynamics using 5.8 million atoms. Flow dynamics and statistics in the presence of the glycocalyx are presented and discussed. Complex dynamic behaviours of the glycocalyx, particularly the sugar chains, are observed in response to blood flow. In turn, the motion of the glycocalyx, including swing and swirling, disturbs the flow by altering the velocity profiles and modifying the vorticity distributions. As a result, the initially one-dimensional forcing is spread to all directions in the region near the endothelial cell surface. Furthermore, the coupled dynamics exist not only between the flow and the glycocalyx but also within the glycocalyx molecular constituents. Shear stress distributions between one-dimer and three-dimer cases are also conducted. Finally, potential force transmission pathways are discussed based on the dynamics of the glycocalyx constituents, which provides new insight into the mechanism of mechanotransduction of the glycocalyx. These findings have relevance in the pathologies of glycocalyx-related diseases, for example in renal or cardiovascular conditions

Mechanotransduction and Ion Transport of the Endothelial Glycocalyx: A Large-Scale Molecular Dynamics Study

In our vessels, the endothelial glycocalyx is the first and foremost barrier directly exposed to the blood in the lumen. The functions of the normal endothelial glycocalyx under physiological conditions are widely accepted as a physical barrier to prevent the abnormal transportation of blood components (e.g. ions, proteins, albumin and etc.) and a mechanosensor and mechanotransducer to sense and transmit mechanical signals from the blood flow to cytoplasm. In this study, a series of large-scale molecular dynamics simulations were undertaken to study atomic events of the endothelial glycocalyx layers interacting with flow. This research is a pioneer study in which flow in the physiologically relevant range is accomplished based on an atomistic model of the glycocalyx with the to-date and detailed structural information. The coupled dynamics of flow and endothelial glycocalyx show that the glycocalyx constituents swing and swirl when the flow passes by. The active motion of the glycocalyx, as a result, disturbs the flow by modifying the velocity distributions. The glycocalyx also controls the emergence of strong shear stresses. Moreover, flow regime on complex surface was proposed based on results from a series of cases with varying surface configurations and flow velocities. Based on the dynamics of subdomains of the glycocalyx core protein, mechanism for mechanotransduction of the endothelial glycocalyx was established. The force from blood flow shear stress is transmitted via a scissor-like motion alongside the bending of the core protein with an order of magnitude of 10~ 100 pN. Finally, the mechanism of flow impact on ion transport was investigated and improved Starling principle was proposed. The flow modifies sugar chain conformations and transfers momentum to ions. The conformational changes of sugar chains then affect the Na+/sugar-chain interactions. The effects of flow velocity on the interactions are non-linear. An estimation in accordance to the improved Starling principle suggests that a physiological flow changes the osmotic part of Na+ transport by 8% compared with stationary transport