Human Vascular System Research Articles

Vascular dysfunction in the diabetic placenta: causes and consequences

The development and functioning of the human fetoplacental vascular system are vulnerable to the maternal diabetic milieu. These vessels are in direct continuum with the fetal vascular system and are therefore also vulnerable to fetal endocrine derangements. Increased angiogenesis, altered junctional maturity and molecular occupancy, together with increased leakiness, constitute a well-described phenotype of vessels in the Type 1 diabetic human placenta and can be related to increased levels of placental vascular endothelial growth factor. The causes of these observed changes, whether maternal hyperglycaemia or fetal hyperinsulinaemia, still remain to be shown in the human placenta. Mechanistic studies using different vascular systems have shown high glucose and insulin to have profound vascular effects, with elevations in vascular endothelial growth factor, nitric oxide and protein kinase C being behind alterations in junctional adhesion molecules such as occludin and vascular endothelial-cadherin and vascular leakage of albumin. The role of advanced glycation products and oxidative stress in this vascular pathology is also discussed. The altered molecular mechanisms underlying the vascular changes in the diabetic human placenta may reflect similar consequences of high glucose and hyperinsulinaemia.

Glycocalyx volume: a critical review of tracer dilution methods for its measurement

A clinical measure of endothelial glycocalyx structure would have great potential importance, because lesions of the glycocalyx may be the first changes to occur in diabetes and in a wide range of vascular diseases. A method recently described by Nieuwdorp et al. for estimating the volume of the luminal glycocalyx of the entire human vascular system would seem to be the first attempt to develop a measure of this kind. It is based on the tracer dilution principle, and this review considers the principles and conditions that underlie this method and the extent to which the conditions appear to have been fulfilled in this case. Our analysis raises two questions about 1) the estimation of the concentration of the tracer (dextran 40) at zero time and 2) the estimation of plasma volume, both of which can be answered by changes in experimental protocol. A third question, concerning the partition coefficient of the tracer between plasma and the fluid within the glycocalyx, cannot be answered at the present time, and until it has been resolved, glycocalyx volume cannot be estimated from the dilution of a macromolecular tracer.

In vivo interactive visualization of four-dimensional blood flow patterns

In this paper we give an overview over a series of experiments to visualize and measure flow fields in the human vascular system with respect to their diagnostic capabilities. The experiments utilize a selection of GPU-based sparse and dense flow visualization algorithms to show the diagnostic opportunities for volumetric cardiovascular phase contrast magnetic resonance imaging data sets. Besides classical hardware accelerated particle and line-based approaches, an extensible tublet-based visualization, a four-dimensional volumetric line integral convolution and a new two-dimensional cutting plane tool for three-dimensional velocity data sets have been implemented. To evaluate the results, several hearts of human subjects have been investigated and a flow phantom was built to artificially simulate distinctive flow features. Our results demonstrate that we are able to provide an interactive tool for cardiovascular diagnostics with complementary hardware accelerated visualizations.

The Hellenistic Royal Court. Court Culture, Ceremonial and Ideology in Greece, Egypt and the Near East, 336-30 BCE

In the Hellenistic empires of Alexander the Great and his successors in Greece, Egypt and the Near East, new forms of court culture and political ideology developed during the last three centuries BCE. Appropriated by Parthian kings and Roman emperors alike, the culture of these Macedonian courts eventually influenced the evolution of royal ideology and court culture in both western Europe and the Islamic East. In this first all-embracing study of the Hellenistic royal court the author endeavours to explain, among other things, the success and long life of Hellenistic royal culture. This study has a broad set-up. It discusses the social, cultural and formal aspects of court society, palace architecture, royal patronage of the arts and sciences, and monarchic representation. The focus is on the three principal Macedonian dynasties: the Antigonids (Macedonia and Greece), Ptolemies (Egypt and the eastern Mediterranean) and Seleukids (Asia Minor, the Near East and Iran). , In Chapter 1 (titled 'Court, kingship and ideology') the methodological en theoretical framework is set out, using recent literature about court culture, state formation and political representation in varying cultures and periods. Hellenistic kingship is defined by the centrality of war and conquest in both ideology and practice. Chapter 2 ('Palaces') discusses the architecture and decoration of royal residences, accentuating the ideological implications, particularly regarding the connection of (royal) palace and (autonomous) city. Chapter 3 ('Court society') discusses the social, formal and political aspects of the court: the courtiers (the so-called 'friends of the king'), the royal family, giving i.a. new interpretations of the position of the queen and the crown prince, as well as the dynamics of faction and succession strife. In Chapter 4 ('Cultural and scientific patronage') a new explanation is given for the remarkable fact that the artistic and scientific life, notably, but not exclusively, at the Ptolemaic Museum at Alexandria, was characterised by intellectual freedom and a preference for innovation, leading e.g. to the formulation of heliocentric theory in astronomy, the first steam engine, the empirical examination of the human vascular and nervous system, and the development of new forms of poetry and scholarship. This chapter also discusses cultural interaction and the significance of the 'Hellenism' of the courts for royal imperial rule. Chapter 4 ('Ritual and ceremonial') extensively deals with public representation: inauguration rituals, ceremonial entries into cities, religious festivals and processions. It will be shown that ritual and ceremonial emphasised the divinity of the ruler, particularly his role as a victorious saviour and bringer of peace, prosperity and order. In the last chapter ('Synthesis: A Golden Age') it is argued, contrary to prevailing opinion, that the Hellenistic monarchies followed the example of their Mesopotamian, Persian and Egyptian predecessors of claiming absolute rulership over world empires that knew no limits. As they also incorporated more 'individualistic' or 'western' aspects of kingship from Greco-Macedonian tradition, the Hellenistic empires developed a form of monarchical representation that was suitable to serve as the foundation for the imperial ideology of the Roman Empire succeeding them.

Noninvasive Detection of the Hemodynamic Stress of Exercise Using the Photoplethysmogram

Exercise induced hemodynamic stress has been studied extensively using a wide range of physiological sensors. While athletes can modulate their training intensity using EKG-based heart rate monitors, there are currently no noninvasive monitors that can be used to ascertain with a high degree of certainty the hemodynamic stress an individual is experiencing because of fatigue or an underlying pathology. We propose that cardiac stress will result in detectable changes in skin blood flow. In a clinical trial with eleven healthy subjects performing the Bruce Protocol treadmill test low frequency waves were observed in the blood flow to both the forehead and ear, but not the finger, using photople- thysmographs (PPG) measured by a pulse oximeter. As volitional fatigue approached, the low frequency (f = 0.05-0.2 Hz) amplitude modulation observed in the PPG became more pronounced; then, within several seconds of the cessa- tion of the protocol, they disappeared. Using a software-based detector, these distinct waves are reliably detected, with a low incidence of false positives, in all subjects before the onset of volitional fatigue. We hypothesize that the low frequency waves observed in the PPG of individuals exercising to volitional fatigue provide a mechanism for noninvasively detecting hemodynamic stress to the human vascular system.

Numerical investigation of blood flow. Part II: In capillaries

In order to understand the normal and pathologic behavior of the human vascular system, detailed knowledge of blood flow and the response of blood vessels is required. In fact the ability to predict the flow hydrodynamics at any site in the vessels can lead to a better understanding of the behavior of blood flow. Simulation can play an important role in understanding the hemodynamic forces. The objective of the present attempt was to simulate the behavior of blood flow in microvessels using computational fluid dynamics (CFD). Numerical analysis is performed using a commercially available CFD package Fluent 6.2 which is based on the finite volume method. A continuum approach is proposed in which fluid structure interaction has been taken into account. Based on limitations imposed by computational resources, a more simplified model based on volume of fluid (VOF) approach is suggested to simulate movements of RBCs in capillaries and also to predict RBCs’ deformation. Three-dimensional incompressible laminar flow fields are obtained by solving continuity and Navier–Stokes equations computationally. It was found that multiphase CFD simulations may give further insight into the dynamic characteristics of blood flow under complex flow conditions.

Computational fluid flow solution over endothelial cells inside the capillary vascular system

AbstractComputational blood flow analysis through glycocalyx located over the endothelial cells in human capillary vascular system is performed. Stable numerical schemes are developed for obtaining approximate solutions to the mixed problem to the partial differential equation with variable space operator to model the blood flow. Numerical techniques are developed by applying a procedure of the solution to the linear difference equation with matrix coefficients. The flow equations inside the core flow region and porous region are established. Discretization is done and the flow velocities in both regions are calculated. The effect of the flow over the glycocalyx is investigated. The wall shear stresses and the drag force over the glycocalyx are calculated. Copyright © 2007 John Wiley & Sons, Ltd.

Geometry of Human Vascular System: Is it an Obstacle for Quantifying Antiangiogenic Therapies?

It is now recognized that all human natural and diseased anatomic systems are characterized by irregular shapes and very complex behaviors. In geometrical terms, tumor vascularity (which is the result of a nonlinear dynamic process called angiogenesis) is an archetypal anatomic system that irregularly fills a 3-dimensional Euclidean space. This characteristic, together with the highly variable nature of vessel shapes and surfaces, leads to considerable spatial and temporal heterogeneity in the delivery of oxygen, nutrients, and drugs, and the removal of metabolites. Although these biologic features have been well established, the quantitative analysis of neovascularity in 2-dimensional histologic sections still fails to view its architecture as a non-Euclidean geometrical object, thus allowing errors in visual interpretation and discordant results concerning the same tumor from different laboratories. We discuss here the tumor-induced vascular system as a fractal object, and what changes this new way of observing may bring to the quantification of effective antiangiogenic therapies.

Balancing prostanoid activity in the human vascular system

The imbalance theory proposes that arterial thrombosis is dependent on a ratio or balance between the cyclooxygenase (COX)-1-dependent generation of thromboxane in platelets and the COX-2-dependent generation of prostacyclin in the endothelium. Accordingly, by reducing endothelium-derived prostacyclin levels, selective COX-2 inhibitors would increase susceptibility to vasoconstriction, platelet activation and atherothrombosis. This imbalance theory has been frequently used to legitimize the potential for increased cardiovascular risk associated with the use of these agents. Surprisingly, the imbalance theory is based not on human vascular biology but on the analysis of urinary prostacyclin metabolites. In this review, I discuss the theory in the context of direct studies of human vascular biology, which indicate that the imbalance theory is based on incorrect assumptions and is not plausible.

Prostanoid Receptors in the Human Vascular Wall

The mechanisms involved in vascular homeostasis and disease are mostly dependent on the interactions between blood, vascular smooth muscle, and endothelial cells. There is an accumulation of evidence for the involvement of prostanoids, the arachidonic acid metabolites derived from the cyclooxygenase enzymatic pathway, in physiological and/or pathophysiological conditions. In humans, the prostanoids activate different receptors. The classical prostanoid receptors (DP, EP1–4, FP, IP, and TP) are localized at the cell plasma or nuclear membrane. In addition, CRTH2 and the nuclear PPAR receptors are two other targets for prostanoids, namely, prostacyclin (PGI2) or the natural derivatives of prostaglandin D2. While there is little information on the role of CRTH2, there are many reports on PPAR activation and the consecutive expression of genes involved in the human vascular system. The role of the classical prostanoid receptors stimulated by PGI2 and thromboxane in the control of the vascular tone has been largely documented, whereas the other receptor subtypes have been overlooked. There is now increasing evidence that suggests a role of PGE2 and the EP receptor subtypes in the control of the human vascular tone and remodeling of the vascular wall. These receptors are also present on leukocytes and platelets, and they are implicated in most of the inflammatory processes within the vascular wall. Consequently, the EP receptor subtypes or isoforms would provide a novel and specific cardiovascular therapeutic approach in the near future.

Vascular Modeling from Volumetric Diagnostic Data: A Review

Reconstruction of vascular trees from digital diagnostic images is a challenging task in the development of tools for simulation and procedural planning for clinical use. Improvements in quality and resolution of acquisition modalities are constantly increasing the fields of application of computer assisted techniques for vascular modeling and a lot of Computer Vision and Computer Graphics research groups are currently active in the field, developing methodologies, algorithms and software prototypes able to recover models of branches of human vascular system from different kinds of input images. Reconstruction methods can be extremely different according to image type, accuracy requirements and level of automation. Some technologies have been validated and are available on medical workstation, others have still to be validated in clinical environments. It is difficult, therefore, to give a complete overview of the different approach used and results obtained, this paper just presents a short review including some examples of the principal reconstruction approaches proposed for vascular reconstruction, showing also the contribution given to the field by the Medical Application Area of CRS4, where methods to recover vascular models have been implemented and used for blood flow analysis, quantitative diagnosis and surgical planning tools based on Virtual Reality. Keywords: Vessel, CT, MRI, Segmentation, 3D

Estrogen actions and in situ synthesis in human vascular smooth muscle cells and their correlation with atherosclerosis

Various epidemiological studies have demonstrated a relatively low incidence of cardiovascular events in premenopausal women and its marked increment after menopause. In addition, estrogens have been postulated to exert direct anti-atherogenic effects via binding to estrogen receptors (ERs) in vascular smooth muscle cells (VSMCs). However, not all postmenopausal women develop atherosclerosis despite decreased levels of serum estrogen. Therefore, it is considered important to examine the status of estrogen metabolism in situ and of ER expression in the human cardiovascular system. Estrone sulfate (E 1S) is a major circulating plasma estrogen that is converted into the biologically active estrogen, estrone (E 1) by steroid sulfatase (STS). E 1 is also sulfated and reverted into E 1S by estrogen sulfotransferase (EST). These two enzymes have recently been shown to play important roles in the in situ estrogen actions of estrogen-dependent human tissues. STS and EST, however, have not been studied in detail in the human vascular system associated with atherosclerotic changes. Therefore, the relative abundance of STS- and EST-immunoreactive protein and mRNA expression in human aorta were evaluated using immunohistochemistry and reverse transcription followed by quantitative polymerase chain reaction in addition to enzyme activity. Furthermore, we evaluated the relative abundance of messenger RNA (mRNA) of both ER subtypes (ERα and ERβ) in the human aorta using reverse transcription followed by quantitative polymerase chain reaction (RT-qPCR), as well as the immunoreactivity of both ERs in VSMCs of human atherosclerotic lesions. STS expression levels were found to be significantly higher in the VSMCs obtained from female aortas with mild atherosclerotic changes than in those with severe atherosclerotic changes and in male aortas regardless of atherosclerotic changes. EST expression levels in the VSMCs of these aortas, however, were significantly higher in female aortas with severe atherosclerotic changes and in male aortas than in female aortas with mild atherosclerotic changes. In addition, the number of ERα and/or ERβ double positive cells in the neointima was higher in female aortas with a mild degree of atherosclerosis than in female aortas with severe atherosclerosis. They indicate that both abundance of these estrogen-metabolizing enzymes in female aorta and relative levels of ER in VSMCs of female neointima may be associated with the status of atherosclerotic changes.

Antithrombogenität humaner Endothelzellen

In the preceeding decades, our understanding of the complexity in our haemostaseologic system has been evolutionized from a purely ex vivo standpoint to an increasingly in vivo oriented approach, by more and more respecting the immense metabolic interactions of our vascular endothelium, mainly thrombin, the central serine protease in our coagulatory system. So far, investigations concerning human endothelium only relied on experiments with embryonic human endothelial cells, derived from umbilical cord veins. The underlying investigation confronts the justified question about the transferability of such embryonic results to the adult vascular system. Micro- and macrovascular endothelial cells were isolated, purified and propagated in pure cultures. Integrated into an established filtration model, their potential to mediate antithrombogenicity was investigated. Surprisingly, immense differences in thrombin-induced antithrombogenicity were demonstrated. This justifies doubts concerning the transferability of HUVEC-based results to the whole human vascular system.

BioSim—a biomedical character-based problem solving environment

Understanding and solving biomedical problems requires insight into the complex interactions between the components of biomedical systems by domain and non-domain experts. This is challenging because of the enormous amount of data and knowledge in this domain. Therefore, non-traditional educational tools have been developed such as a biological storytelling system, animations of biomedical processes and concepts, and interactive virtual laboratories. The next-generation problem solving tools need to be more interactive to include users with any background, while remaining sufficiently flexible to target open research problems at any level of abstraction, from the conformational changes of a protein to the interaction of the various biochemical pathways in our body. Here, we present an interactive and visual problem solving environment for the biomedical domain. We designed a biological world model, in which users can explore biological interactions by role-playing “characters” such as cells and molecules or as an observer in a “shielded vessel”, both with the option of networked collaboration between simultaneous users. The system architecture of these “characters” contains four main components: (1) bio-behavior is modeled using cellular automata; (2) bio-morphing uses vision-based shape tracking techniques to learn from recordings of real biological dynamics; (3) bio-sensing is based on molecular principles of recognition to identify objects, environmental conditions and progression in a process; (4) bio-dynamics implements mathematical models of cell growth and fluid-dynamic properties of biological solutions. The principles are implemented in a simple world model of the human vascular system and a biomedical problem that involves an infection by Neisseria meningitides where the biological characters are white and red blood cells and Neisseria cells. Our case studies show that the problem solving environment can inspire user's strategic, creative and innovative thinking.

One-dimensional modelling of a vascular network in space-time variables

In this paper a one-dimensional model of a vascular network based on space-time variables is investigated. Although the one-dimensional system has been more widely studied using a space-frequency decomposition, the space-time formulation offers a more direct physical interpretation of the dynamics of the system. The objective of the paper is to highlight how the space-time representation of the linear and nonlinear one-dimensional system can be theoretically and numerically modelled. In deriving the governing equations from first principles, the assumptions involved in constructing the system in terms of area-mass flux (A,Q), area-velocity (A,u), pressure-velocity (p,u) and pressure-mass flux(p,Q) variables are discussed. For the nonlinear hyperbolic system expressed in terms of the (A,u) variables the extension of the single-vessel model to a network of vessels is achieved using a characteristic decomposition combined with conservation of mass and total pressure. The more widely studied linearised system is also discussed where conservation of static pressure, instead of total pressure, is enforced in the extension to a network. Consideration of the linearised system also allows for the derivation of a reflection coefficient analogous to the approach adopted in acoustics and surface waves. The derivation of the fundamental equations in conservative and characteristic variables provides the basic information for many numerical approaches. In the current work the linear and nonlinear systems have been solved using a spectral/hp element spatial discretisation with a discontinuous Galerkin formulation and a second-order Adams-Bashforth time-integration scheme. The numerical scheme is then applied to a model arterial network of the human vascular system previously studied by Wang and Parker (To appear in J. Biomech. (2004)). Using this numerical model the role of nonlinearity is also considered by comparison of the linearised and nonlinearised results. Similar to previous work only secondary contributions are observed from the nonlinear effects under physiological conditions in the systemic system. Finally, the effect of the reflection coefficient on reversal of the flow waveform in the parent vessel of a bifurcation is considered for a system with a low terminal resistance as observed in vessels such as the umbilical arteries.

Steroid Sulfatase and Estrogen Sulfotransferase in the Atherosclerotic Human Aorta

Various epidemiological studies have demonstrated a relatively low incidence of cardiovascular events in premenopausal women and its marked increment after menopause. In addition, estrogens have been postulated to exert direct anti-atherogenic effects via binding to estrogen receptors in vascular smooth muscle cells (VSMCs). However, not all postmenopausal women develop atherosclerosis despite decreased levels of serum estrogen. Therefore, we believe it is important to examine the status of estrogen metabolism in situ in the human cardiovascular system. Estrone sulfate (E1S) is a major circulating plasma estrogen that is converted into the biologically active estrogen, estrone (E1) by steroid sulfatase (STS). E1 is also sulfated and reverted into E1S by estrogen sulfotransferase (EST). These two enzymes have recently been shown to play important roles in the in situ estrogen actions of estrogen-dependent human tissues and various sex steroid-dependent tumors. STS and EST, however, have not been studied in detail in the human vascular system associated with atherosclerotic changes. In the present study, we evaluated the relative abundance of STS- and EST-immunoreactive protein and mRNA expression in human aorta using immunohistochemistry and reverse transcription followed by quantitative polymerase chain reaction in addition to enzyme activity. STS expression levels were found to be significantly higher in the VSMCs obtained from female aortas with mild atherosclerotic changes than in those with severe atherosclerotic changes and in male aortas regardless of atherosclerotic changes. EST expression levels in the VSMCs of these aortas, however, were significantly higher in female aortas with severe atherosclerotic changes and in male aortas than in female aortas with mild atherosclerotic changes. We believe it is important to examine factors regulating the expression and activity of these estrogen-metabolizing enzymes in the human aorta. Various cytokines have been proposed to function as regulators of these enzymes in other tissues. In the present study, we studied the effects of interleukin (IL)-1beta, known to be produced in human atherosclerotic lesions, on the expression of these enzymes using cultured human VSMCs originally obtained from a female patient. IL-1beta markedly inhibited the expression of STS mRNA and enzyme activity, but stimulated the expression of EST mRNA and enzyme activity. In addition, IL-1beta also reduced E2 production from E1S and E1 in VSMCs. Results from the present study seem to suggest that the expression levels of both STS and EST mRNA and activity may be significantly associated with the degree of atherosclerotic changes in the female aorta, which may be related to cytokines produced in situ, such as IL-1beta, in human atherosclerotic lesions.

3DVIEWNIX-AVS: a software package for the separate visualization of arteries and veins in CE-MRA images

Our earlier study developed a computerized method, based on fuzzy connected object delineation principles and algorithms, for artery and vein separation in contrast enhanced Magnetic Resonance Angiography (CE-MRA) images. This paper reports its current development—a software package—for routine clinical use. The software package, termed 3DVIEWNIX-AVS, consists of the following major operational parts: (1) converting data from DICOM3 to 3DVIEWNIX format, (2) previewing slices and creating VOI and MIP Shell, (3) segmenting vessel, (4) separating artery and vein, (5) shell rendering vascular structures and creating animations. This package has been applied to EPIX Medical Inc's CE-MRA data (AngioMark MS-325). One hundred and thirty-five original CE-MRA data sets (of 52 patients) from 6 hospitals have been processed. In all case studies, unified parameter settings produce correct artery–vein separation. The current package is running on a Pentium PC under Linux and the total computation time per study is about 3 min. The strengths of this software package are (1) minimal user interaction, (2) minimal anatomic knowledge requirements on human vascular system, (3) clinically required speed, (4) free entry to any operational stages, (5) reproducible, reliable, high quality of results, and (6) cost effective computer implementation. To date, it seems to be the only software package (using an image processing approach) available for artery and vein separation of the human vascular system for routine use in a clinical setting.

Hypoxia activates the human placental vascular endothelial growth factor system in vitro and in vivo: Up-regulation of vascular endothelial growth factor in clinically relevant hypoxic ischemia in birth asphyxia

Objective: We investigated the influence of acute hypoxia on the placental vascular endothelial growth factor system in vitro and in vivo in acute birth asphyxia compared with pregnancies that were complicated by preeclampsia and with healthy control subjects. Study design: Messenger RNA levels for vascular endothelial growth factor, flt-1, and KDR were measured by TaqMan real-time polymerase chain reaction in human placental choriocarcinoma cells (BeWo) that were exposed to hypoxia (1% oxygen, 5% carbon dioxide, 94% nitrogen) and in placental tissue of neonates with birth asphyxia (n = 20), newborn infants of mothers with preeclampsia (n = 20), and gestational age-matched control subjects. Immunhistologically, placental vascular endothelial growth factor protein expression was compared among the groups. Results: In BeWo cells, vascular endothelial growth factor, flt-1 and KDR messenger RNA increased in a time-dependent manner in response to hypoxia. In vivo, vascular endothelial growth factor/β-actin and KDR/β-actin messenger RNA were significantly higher in placental tissue of newborn infants with severe hypoxic-ischemic encephalopathy than with newborn infants with mild or no hypoxic-ischemic encephalopathy and control subjects. In chronic placental hypoxia (preeclampsia), vascular endothelial growth factor and both receptors were found to be up-regulated. Increased placental vascular endothelial growth factor expression was confirmed by immunohistologic examination. Conclusion: The vascular endothelial growth factor system is up-regulated in response to placental hypoxia and is assumed to be a potential early indicator of severe birth asphyxia. (Am J Obstet Gynecol 2003;188: 517-23.)

Regulation of the swelling mechanism in the inferior turbinate of human nasal mucosa

The swelling mechanism of human nasal mucosa is based on a complicated vascular system and regulated by a variety of classical and peptidergic transmitters as well as by endothelial transmitters. The aim of this study was to elucidate this mechanism taking into account the distribution of these substances and the morphology of the different vessels. Tissue specimens of human inferior turbinates were evaluated by light and electron microscopy. We used frozen sections to localize enzymes of the transmitter synthesis by histochemical and immunocytochemical methods. The distribution of classical neurotransmitters, neuropeptides (calcitonin-gene-related-peptide, neuropeptide Y, substance P and vasoactive intestinal polypeptide), enzymes producing neuronal NO (neuronal nitric oxide synthase, nicotine-amid-adenine-dinucleotide-phosphate-diaphorase) as well as endothelial transmitters such as endothelin and endothelial nitric oxide were examined. For ultrastructal examination the specimens were fixed in glutaraldehyde und osmium tetroxide, embedded in araldide, cut and double contrasted. Most of the axons and immunoreactivity of transmitters were located in the arterial part of the human nasal vascular system. In venous vessels only a spare innervation was observed, whereas in the subendothelial muscular bolsters of the cushion veins a rich nerve supply could be detected. Near the fenestrated subendothelial and periglandular capillaries no axons were found. Nasal vasculature is supplied by a equilibrated aminergic and cholinergic innervation. Mainly arterial vessels showed reactions to antibodies directed against endothelial transmitters. Because of the dense innervation of arteries and subendothelial venous muscular bolsters we conclude that the swelling mechanism of human nasal mucosa is mainly regulated by these structures. A dual (endothelial and neuronal) control exists in arterioles whereas the control in the subendothelial muscular swellings of the cushion veins appears to be mainly neuronal. The swelling of the nasal mucosa is achieved by an simultaneous relaxation of all smooth muscle cells, which leads to dilatation of arteries as well as venous sinuses. The drainage of the vascular bed is reduced by the venous muscular bolsters protruding into the lumen of the venous sinuses. Vice versa, a contraction of all smooth muscle cells leads to a contraction of the arteries and, consecutively, to a reduction of blood supply. Simultaneously the muscular bolsters are torn out of the lumen of venous sinusoids allowing blood drainage to be increased: nasal concha decongests.

Relationship of the 20S Proteasome and the Proteasome Activator PA28 to Atherosclerosis and Intimal Hyperplasia in the Human Vascular System

Down-regulation of the proteasome activator PA28 results in abnormal proteasome activation and has been implicated in the development of intimal hyperplasia (IH) in animal models. Demonstration of proteasome and PA28 expression has not yet been documented in the human vascular system. This study sought to define the distribution of the 20S proteasome and its activator PA28 in human vessels and determine the relationship between the expression of the proteasome and PA28 and the development of atherosclerosis and IH. Vascular biopsies were obtained from 70 patients at the time of surgery, were snap frozen and sectioned in 5-micron sections, and prepared using standard histological techniques. The immunoperoxidase technique was used to identify 20S proteasome and PA28 expression in diseased and normal human arteries and veins as well as in patent bypass grafts with and without IH. Expression was graded by a blinded pathologist (scale: 1-4). Repeat quantification of the immunopositive cells was also performed. Expression of 20S proteasome and PA28 was identified in all vascular tissues examined. The proteins were identified predominately within the cytoplasm of vascular smooth muscle cells and endothelial cells. PA28 was more intensely expressed in quiescent regions of the vessel wall as compared to areas undergoing active proliferation and remodeling. PA28-mediated activation of the proteasome may be necessary to maintain normal cellular homeostasis and prevent excessive cellular proliferation in the human vascular system. Abnormalities of proteasome activation may have a significant role in the development of atherosclerosis and IH.