Hepatic Microvascular System

The hepatic microvascular system comprises all blood and lymphatic vessels immediately involved in the delivery and removal of fluids to and from the hepatic parenchyma, namely, portal venules, hepatic arterioles, sinusoids, central venules, and lymphatics. Figure 2 is a diagram illustrating the afferent and efferent microvascular connections to the sinusoids within a single hepatic lobule. Most blood enters the sinusoids from portal venules. These inlets are reported to be guarded by...

Functional Aspects of Cigarette Smoke Induced Microvascular Dysfunction

In terms of functional effects of the cigarette smoke impaired microvasculature, the accessibility of the skin microcirculation to noninvasive diagnostic techniques (i.e., plethysmography, nailfold microscopy, laser Doppler fluxmetry) has resulted in an abundant literature on the effect of cigarette smoking on skin perfusion in humans and experimental animals. These studies have found that baseline blood flow in the skin of smokers is reduced either permanently and or after smoking one or more...

Antithrombotic Properties of Statins

Activation of thrombotic processes contributes to microvascular dysfunction in a variety of disease states such as sepsis and ischemia-reperfusion. Statins inhibit platelet activity by several mechanisms, including increased endothelial NO and adenosine release and decreased platelet thromboxane production and cholesterol content. Tissue factor expression and activity in response to thrombin is reduced in EC by simvastatin at concentrations as low as 100 nM. The fibrinolytic system may also be...

ABC Transporters

Transporters belonging to the ATP-Binding Cassette (or ABC) family of proteins have the ability to transport substrates across cellular membranes against a concentration gradient using the energy of ATP hydrolysis. They are so called because of their distinctive ATP-binding domains, which contain highly conserved sequences, Walker A and Walker B and an additional ABC signature sequence. ABC proteins constitute the largest subclass of transmembrane proteins and are expressed ubiquitously in all...

Growth and Structure of the Lymphatic Tree

Work on the lymphatic system began in the 17th century, and by the beginning of the 19th century, the anatomy of most of the lymphatic system had been described. Much of the work carried out late in the 19th century and in the first half of the last century was aimed at determining the embryonic origin of lymphatic endothelium. Two theories were proposed. The first suggested that lymphatic endothelium derives by sprouting from blood vascular (venous) endo-thelium, the so-called centrifugal...

Endogenous Defenses against ROS

This enzyme catalyzes the dismutation of superoxide to hydrogen peroxide (H2O2) Several isozymes of SOD exist (1) Cu Zn-SOD, a cytosolic form (2) Mn-SOD, which is localized within mitochondria and (3) extracellular SOD (ecSOD). The last is released from cells and binds to sulfated polysaccharides along the cell surface. As a result, ecSOD plays a particularly important role in defense against ROS released from leukocytes adherent to the vascular endothelium. Although conflicting results have...

Fenestrae Function

Attempts to investigate the permeability properties of fenestrae were initiated by Clementi, Palade, Simionescu, and Pino using tracer perfusion studies. Horseradish peroxidase ( 4nm in diameter) proved to be readily permeable through diaphragmed fenestrae of the intestinal mucosal capillaries and the ocular choriocapillaris, whereas larger tracers such as ferritin ( 11 nm in diameter), or dextrans and glycogens, were variably permeable. These findings fit remarkably well with data developed by...

Neutrophils and Pulmonary Endothelial Cells Are Targets to Treat ALI

Activated neutrophils are obviously playing role in the lung microvascular pathophysiology. The removal of neutrophils by filtration, by anti-neutrophil antibody, or by chemical agents such as nitrogen mustard is beneficial for the experimental ALI. Antiadhesion molecule antibodies are also beneficial 8 . We have reported that the inhibition of L-selectin attenuated ovine ALI 9 , but anti-P-selectin antibody did not. Since P-selectin is induced at very early time points and decreases soon after...

Future Research

Microvascular endothelial cells form the semipermeable wall of capillaries and venules that are essential for regulating blood-tissue exchange. Although clinical studies suggest that increased transvascular flux of fluid and proteins in pre-eclampsia might be due to endothelial barrier failure in pre-eclampsia, the molecular mechanisms underlying the pathological regulation of microvascular endothelium remain to be investigated. Transendothelial movement of fluid and solutes is a dynamic...

Skin Microvasculature and Techniques for Measuring Skin Blood Flow

Skin microvasculature is organized as two horizontal plexuses, with one located 1 to 1.5 mm below the skin surface and the other at the dermal-subcutaneous junction. The lower plexus is formed by perforating vessels from the underlying muscles and subcutaneous fat. The arterioles and venules in the fat lobules are identical in size and structure to those of the lower horizontal plexus. Descending venules and ascending arterioles connect the two plexuses and are arranged in pairs and supply the...

Model of Cremaster Muscle Isograft and Allograft Transplant

After transplantation, two patterns of tissue damage can occur during allograft rejection. One is caused by cellmediated or antibody-mediated damage. The second is due to the tissue ischemia and surgical trauma causing microvascular destruction 9 . Since these patterns are dependent on the interactions between the allograft endothelium as well as allograft and recipient immune systems, a quantitative assessment of the microvascular events occurring during allograft rejection is crucial. The...

Peritoneal Cavity

Transcellular Pore (Aquaporin) r < 0.5 nm Small Pore , r 4.0-6.0 nm V- * Figure 4 Pore-matrix theory of transendothelial transport. See text for details. Figure 4 Pore-matrix theory of transendothelial transport. See text for details. multicompartment model that includes this division of the circulation and which is particularly useful in consideration of drug absorption and mathematical modeling. Peritoneal Microcirculation Involved in Transport The classic description of the peritoneal...

Konstantin G Birukov

Department of Medicine, Johns Hopkins University, Baltimore, Maryland. Vascular endothelial cells play significant roles in regulating vascular functions in health and disease. Mechanical forces such as shear stress and cyclic stretch sequentially activate mechanosensors, intracellular signaling pathways, specific transcription factors, cytoskeletal remodeling, and the expression of genes and proteins and, as result, profoundly modulate endothelial cell functions. This article describes the...

Hans Anton Lehr

Institute of Pathology, University of Mainz, Medical Center, Mainz, Germany Cigarette smoke contains large amounts of carcinogenic and cocarcinogenic substances that explain the increased burden of malignant tumors in smokers, particularly in the lungs, the upper gastrointestinal system, and the urinary bladder. Nonneoplastic diseases associated with cigarette smoking include chronic bronchitis and pulmonary emphysema, gastrointestinal ulcers, and a significantly increased risk of...

The Ephs and Ephrins

The Eph family of RTKs comprise 15 members. They are activated by ligands, the ephrins (of which there are 9), which are cell surface bound. This system functions in short-range cell-to-cell communication. The ephrins are Figure 2 FGFR-1 Signaling in the Endothelium. This schematic figure shows the main tyrosine phosphorylation sites in FGFR-1. Shaded boxes in the intracellular portion of the receptor denote the kinase domain. Signaling intermediates are shown adjacent to phosphotyrosine...

Dan D Hershko and Michael M Krausz

Department of Surgery A, Rambam Medical Center, Haifa, Israel The extracellular fluid volume is maintained within narrow limits in normal human subjects, despite day-to-day variations in the dietary intake of salt and water. Plasma volume, in turn, is determined by the total extracellular fluid volume, and the partitioning of this volume between the extravascular fluid and the intravascular compartments also remains remarkably constant. The relationship of extracellular volume and, in...

The Implications of a New Microvascular Paradigm

Since the time of Malpighi in the late 17th century, scientists have understood capillary networks to consist of a unique class of tiny hair-like microvessels linking arteri-oles to venules. Part of what distinguished capillaries operationally from all other vessel types was that they were neither arterial nor venous and could therefore function as a vascular crossroads for gas and metabolite exchange at the tissue level. In the late 1970s and early 1980s, however, a series of studies out of...

Wound Reepithelialization

Rapid wound epithelialization, the migration of ker-atinocytes to seal an open wound, is considered by many to be a good predictor of successful wound healing. A fully epithelialized wound is more likely to heal. Keratinocytes begin this process by invading the provisional clot made of fibrin and fibronectin. Plasmin is upregulated soon after wounding, presumably for breaking down the fibrin clot. Indeed, plasminogen knockout mice demonstrate significantly diminished wound reepithelialization 4...

PDGFB Pericyte Recruitment and Vessel Maturation

PDGF-B is the most characterized member in the PDGF family. Although first discovered as a secretory product of platelets during coagulation, PDGF-B is also expressed in many other cell types, such as endothelial cells, macrophages, smooth muscle cells, fibroblasts, glial cells, neurons, tumor cells, and possibly others. Expression of PDGF-B is constitutive in immune and nerve cells, whereas inducible expression of PDGF-B most likely occurs in other cell types. The actions of PDGF-B can occur...

Regulation of the Endothelial Cytoskeleton by Statins

The primary function of the Rho signaling proteins is regulation of the cytoskeleton. In the endothelium, cytoskeletal filament rearrangement determines barrier function. In response to certain stimuli, such as thrombin, RhoA is activated and localized to the membrane. Rho-kinase is consequently activated, leading to the formation of actin stress fibers, focal adhesions, intercellular gap formations, and disruption of EC barrier function. Simvastatin (5 mM for 16 to 24 hours) attenuates...

Applying the Input Output Analogy to Cardiac Microvasculature in Health

The notion that the endothelium represents a series of input-output devices is helpful when considering the vascu-lature or endothelium during development and in the postnatal period. A consideration of cardiac development is beyond the scope of this chapter. The following section will focus on the adult cardiac endothelium. The endothelium of the coronary and resistance vessels has presumably evolved to optimize the transport blood (oxygen and nutrients) to the myocardium. Compared with...

Intrinsic Regulation of Complement Activation

The rapid spontaneous decay of the multimolecular enzymes of each pathway that cleave C3 and C5 serves as the primary feature that prevents a complement activation event from amplifying uncontrollably (Table 1). Furthermore, several highly specific complement regulatory proteins exist that each inhibit portions of the complement activation cascades. In addition to limiting amplified complement activation, there seem to be three more functions served by these control proteins. One is to prevent...

Permeability Coefficients

For practical purposes, there are three permeability coefficients. Two of these describe the permeability to a particular solute (the diffusional permeability and the solute reflection coefficients) and the third describes fluid permeability (the hydraulic permeability). The Solute Diffusional Permeability Coefficient The solute diffusional permeability, Pd, is defined under conditions where there are no net movements of fluid through microvascular walls. It is the transport of the solute...

Role in Periodontal Disease

During the progression of periodontal disease, the periodontal vasculature is profoundly affected and there is evidence that inflamed tissue enhances the expression of inflammatory mediators, which in their turn may promote angiogenesis. It has been found that there are greater amounts of VEGF in gingival crevicular fluid collected from clinically diseased sites than in fluid from healthy sites. VEGF production in gingival fibroblasts and periodontal ligament fibroblasts may enhance vascular...

Evidence for Capillary Arteriolar Communication

The majority of experimental evidence for communication along the capillary is indirect. Using amphibian and mammalian skeletal muscle preparations, our laboratory has shown that micropipette application of a minute amount of various vasoactive agents (norepinephrine, phenylephrine, acetylcholine, bradykinin, adenosine analog NECA, KCl) on capillaries 300 to 500 mm away from the feeding arteriole causes constriction dilation of this arteriole and ensuing reduction increase in blood flow in...

Differential Regulation of Permeability in the Microvasculature

Having described the general mechanisms through which the cytoskeleton regulates endothelial permeability, we will now outline specific characteristics intrinsic to microvascu-lar barrier function. Although the endothelium was initially regarded as relatively homogeneous throughout the vascula-ture, important phenotypic and functional differences are now appreciated at various sites along the vascular tree. These differences account for the tremendous physiologic variability observed in...

The Marrow Sinus

The sinus is the exclusive site of exchange between the hematopoietic and the circulating blood. It is at this sole location that mature hematopoietic cells (polymorphs, platelets, and red cells) enter the circulation to finalize their life cycle as blood cells and that hematopoietic stem cells (HSCs) enter the marrow parenchyma during engraftment. BM sinus ECs express in a specific way a number of molecules. Some cell adhesion molecules (CAMs), such as E-selectin or vascular cell adhesion...

Mechanical Strain Shear Stress and Flow

Vascular endothelial cells withstand constant mechanical shear force of blood flow and can adapt in response to acute and chronic changes in hemodynamic forces. These physiological changes in the vascular wall are regulated by the IF cytoskeleton and IF-associated proteins, which not only serve as internal scaffolding for the endothelial cell, but are also linked to the plasma membrane, contacts to adjacent cells and to the basement membrane. Vimentin protein expression is higher in...

Neuropilin Function in Developmental Angiogenesis

There is strong evidence from transgenic mouse studies that NRPs mediate angiogenesis. Mice overexpressing NRP1 were embryonic lethal and displayed several vascular abnormalities, such as excess capillaries and blood vessels, dilation of blood vessels, hemorrhage, and malformed hearts. The chimeric embryos appeared redder than their normal counterparts, suggesting that blood vessels were leaky, which was possibly caused by enhanced vascu lar permeability activity of VEGF165. It was concluded...

NO and the Homeostasis of the Blood Cell Interaction with the Vessel Wall

Preserving a Nonthrombogenic Surface of the Endothelium In addition to the role of NO as a vasodilator, NO in the microcirculation can prevent platelets from adhering to the endothelium and can assist with the disaggregation of activated platelets to the endothelium or underlying basement membrane (Figure 1). More recently, this concept was unequivocally demonstrated in mice deficient for eNOS 6, 7 . Bleeding times were decreased in eNOS (- -) mice and platelet adhesion to venules was increased...

Hypercholesterolemia and Arterioles

Under normal physiological conditions, basal NO production by endothelial cells maintains vascular tone and inhibits inflammation. However, during hypercholes-terolemia, several events occur that negatively influence the vasodilatory role of NO in arterioles. Although the concentration of L-arginine, the substrate for NO synthase (NOS), is not reduced during hypercholesterolemia, the interaction between L-arginine and endothelial NOS may be blocked by the endogenous inhibitor asymmetric...

Integration of Metabolic Response Pathways

In addition to considerations about which control mechanisms for arteriolar responses reside on SMCs versus ECs, it has become apparent that these two cell types can be closely coupled, thus enabling the arteriolar wall to act as a syncytium. In small arterioles there are gap junctions between adjacent ECs and between adjacent SMCs in addition the two cell types are connected by myoendothelial gap junctions. This arrangement allows signals to spread axially along the vessel, and also to be...

Platelet Endothelial Interaction Following Endothelial Stimulation

In a second set of experiments on the microcirculation of LLC-1 carcinoma and BFS-1 fibrosarcoma, platelet-endothelial interactions were assessed in response to endothelial stimulation by calcium ionophore A23187. Calcium ionophore A23187 increases intracellular calcium concentration and thereby induces the release of adhesion molecules vWF and P-selectin from endothelial cell-specific Weibel-Palade bodies sparing endothelial integrity. The secretion of Weibel-Palade bodies from endothelial...

Angiogenesis in Vein Grafts Impact of the External Stent

Surgery, ipso facto, elicits MV damage. In turn, the efficacy of revascularization may be axiomatic in determining the outcome of surgical procedures. One clinical scenario in which many of these factors come into play is in coronary artery bypass graft surgery (CABG) using autologous saphenous vein. CABG involves the removal of the vein from the patient, which is then implanted by anastomosis into the aortic arch and then below an atherosclerotic lesion in the coronary artery, effectively...

Pathophysiology of the Hepatic Microcirculation

Significant interactive roles for endotoxin, cytokines, chemokines, reactive free radicals, nitric oxide (NO), endothelin (ET-1), carbon monoxide (CO), sinusoidal lining cells, leukocytes, and platelets have been demonstrated in the pathophysiology of hepatic microvascular disturbances and parenchymal injury resulting from infection, toxicants, and ischemia reperfusion following hemorrhage or liver transplantation. The responses of the hepatic microvascula-ture are of two basic types (a) an...

The Role of the Mitogen Activated Protein Kinase MAPK Pathway

(a) The mechanisms by which TNF-a triggers microtubule network disassembly, followed by actin cytoskeleton rearrangement and intercellular junction changes, include the activation of the MAPK pathways. The MAPK pathways are important intracellular signaling pathways that are activated by TNF-a-induced ligation of the TNF receptors, TNFR1 (p55) and to a lesser extent TNFR2 (p75). Each component of the MAPK pathways is differentially recruited by specific stimuli resulting in kinase-specific...

Capillary Basement Membrane Thickness in Health and Disease

TEM studies of CBMs in humans and other vertebrates show that regardless of animal age or health, they are continuous along the length of the microvessel and closely adhere to their parent cell types as described previously. CBM thickness, however, is widely variable within and between tissue types both in health and disease. It is now clear that in many tissues, CBM thickness is a normal function of age and is considered a biomarker for aging. However, thickness increases with age are not seen...

Morphological Aspects of Human Placentation

The complex anatomy of the placenta has made studies of the entire organ difficult. Commonly the placenta is depicted as a simple, pancake-shaped sponge connecting the embryo fetus to the uterus. This portion of the placenta, which is expelled from the uterus during delivery, is easy to obtain and, consequently, frequently studied. But the most interesting part of the placenta is rarely seen. This portion, which lies buried within the uterine wall, separates from the rest of the placenta during...

Control of Motility by ECM

It is well known that ECM plays a central role in microenvironmental control of cell motility based on its ability to chemically mediate cell adhesion. In addition, capillary endothelial cells must increase ECM degradation to initiate cell outgrowth and also must maintain ongoing ECM synthesis and deposition to sustain progressive cell migration during both angiogenesis and healing of large vessel endothelial monolayers. Importantly, recent work has revealed that the physical properties of the...

Pulmonary Arterial Hypertension

A major disorder involving the pulmonary microvasculature and eicosanoids is pulmonary arterial hypertension (PAH). PAH primarily affects the small pulmonary arteries with a diameter of less than 100 microns. Pathological changes include medial hypertrophy, intimal proliferation, in situ thrombosis, and plexiform lesions, the latter likely a disordered attempt at neovascularization. PAH may occur without an associated disorder, primary pulmonary hypertension (PPH), or in association with...

Michael Simons and 2Mark J Post

1The Angiogenesis Research Center, Section of Cardiology, Departments of Medicine and Pharmacology and Toxicology, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 2Department of Physiology and Biomedical Technology, University of Maastricht, Maastricht, The Netherlands Disruption of blood flow to tissues leads to reduction in oxygenation and deterioration of function. In the myocardium this leads to reduction in myocardial contractility with subsequent...

Lipoxygenases in ECs

Lipoxygenases (LOX) are nonheme iron-containing enzymes that catalyze arachidonate or linoleate oxidation to form a series of lipid hydroperoxides. In mammalian cells, several isoforms are known, named by their position of oxygen insertion into arachidonate. Lipoxygenases contain a single nonheme iron that alternates between Fe2+ and Fe3+ during catalysis. Resting enzyme predominantly exists as the reduced form, requiring oxidation by hydroperoxides before dioxygenation can occur. Vascular and...

Renewed Perspective on the Physiopathology of the Lymphatic System

Lymph is essentially protein-rich interstitial fluid, which in turn is an ultrafiltrate of plasma. Unique to lymphatic capillaries are overlapping intercellular junctions that are formed by the extensive superimposition of adjacent LECs. LECs also have anchoring filaments, which link the basolat-eral plasma membrane to the adjacent extracellular matrix. As interstitial pressure rises, collagen fibers and other matrix components are forced apart. This in turn pulls on anchoring filaments, the...

Vascular Connexin Expression

Connexin expression is sensitive to cell state and varies with cell and vessel type. Connexin protein expression in situ is typically defined by immunohistochemical localization or by immunoblot. However, cross-reactivity between antibodies, particularly cross-reactivity of anti-Cx40 antibodies to Cx43, is a potential concern when considering analysis of connexin expression in the vasculature. Gap junctions are more prominent in large than small vessels. Interendothelial and inter-smooth muscle...

Three Pore Theory

Three-pore theory explains water and solute transport across the peritoneal microvessel during peritoneal dialysis. For this transport process, there are three kinds of pores a large number of small pores (radius 40 to 50 ) for low molecular weight, a very low number of large pores (radius 250 ) for macromolecules, and ultrasmall pores (radius 3 to 5 ) for water transport but rejecting the transfer of solutes. Aquaporins, especially aquaporin-1, which was identified recently, are the proteins...

Xanthine Oxidoreductase An Enigmatic Enzyme

Considerable research has been focused on XOR and its role in health and disease. Yet the extent of XOR involvement in disease processes has been debated over several decades. Questions remain concerning the low level of XOR activity in human tissues and about the exact significance of the conversion of XOR from the dehydrogenase to the oxidase form. However, there is no doubt that the enzyme can generate ROS and can be upregulated under a variety of pathological stimuli. Low basal XOR activity...

Problems with Hemoglobinbased Blood Substitutes in the Microcirculation

Role of Hemoglobin as a Nitric Oxide Scavenger Many experimental studies have reported an increase in blood pressure after administration of hemoglobin solutions, and pilot clinical trials have confirmed this observation. One theory to explain this phenomenon is that arterioles constrict due to removal of the endogenous vasodilator, nitric oxide (NO), by the hemoglobin. This theory is supported by studies showing that administration of the NO precursor, L-argi-nine, at the same time as DCLHb...

Introduction

Physiological hemostasis and pathological thrombosis take place within a complex in vivo milieu. The complex variables that modulate prohemostatic and prothrombotic responses are probably best organized by examining them within Virchow's triad. Virchow's triad reminds us that hemostasis and thrombosis are regulated by the simultaneous interactions among blood (cells and soluble constituents), blood vessel (endothelium, subendothelium, and smooth muscle), and blood flow (related to diameter,...

The Relationship between PSTR and Alterations of Peritoneal Microvessels in PD Patients

As described earlier, many reports have been published with the theory that peritoneal transport is related to peritoneal vascular surface area however, there is only one report, from the present authors, that investigated this phenomenon as the clinical fact. We reported alterations in the peritoneal capillary and postcapillary venule (i.e., the main part of water and solute transport named microvessel in the report) in biopsy specimens of peritoneum obtained from PD patients. The parietal...

From Phage to Fish

In the late 1960s George Streisinger began working with zebrafish at the University of Oregon with the goal of devel oping a vertebrate genetic model system comparable to the fly. Streisinger had worked with bacteriophage at Caltech during the critical foundation period of the molecular era, when the basic DNA-RNA-protein story was being established. His studies at Caltech involved a mutational approach to evaluate the genetic code, including its structure and the process of translation in the...

Microtubules and Response to Shear Stress

Vascular endothelial cells are exposed to constant physiological shear stress from blood flow. Microtubules contribute to the stability of microvascular cells via intracellular distribution changes concomitant with EC migration and motility. Within the endothelial cell in an intact quiescent monolayer, microtubules are distributed in an extensive array radiating from the centrosome, or MT organizing center (MTOC), which is randomly oriented around the nucleus. Stress on the monolayer, such as...

Molecular Structure

Currently a total of 23 enzymes out of 29 MMPs have been identified in humans. Five MMPs are shorter isoforms of full-length enzymes, and one is annotated as MMP-like1 protein. Additionally, several plant and nonvertebrate MMPs have been found and characterized. All MMP family members share a similar multidomain structure. The general structural pattern consists of a prodomain, a catalytic domain, a hinge region, and a hemo-pexin domain. The prodomain comprises a signal peptide of about 20...

Impaired Relaxation of Arterioles to Vasodilator Stimuli

In addition to an enhanced response to vasoconstrictor stimuli, arterioles of hypertensive animals exhibit an impaired relaxation in response to a variety of vasodilator stimuli including hypoxia, shear stress, and endothelium-dependent vasodilators, such as acetylcholine (ACh). Impaired relaxation of arterioles to endothelium-dependent vasodilator stimuli such as ACh has also been demonstrated in human hypertensive patients. The impaired vascular relaxation in hypertensive individuals has been...

Activation of Metalloproteinases

The final products of MMP gene translation are inactive forms of enzymes such as zymogens or proMMPs. Functionally, the active form of MMPs requires exposure of the active catalytic center, which occurs via a series of conformational changes. The active site containing a zinc-binding motif and surrounding amino acids consists of a cleft along the catalytic domain. In the latent form of the enzyme, the polypeptide tail of the prodomain region covers the catalytically competent cleft. The...

Tao Rui Gediminas Cepinskas and Peter R Kvietys

Vascular Biology Inflammation Program, Lawson Health Research Institute, London, Ontario, Canada Reperfusion of ischemic myocardium results in pathological changes in the heart, such as myocardial stunning, an acute inflammatory response, and infarction. Paradoxically, pretreatment of the heart with an ischemia-reperfusion (I R) challenge confers protection against a subsequent I R insult. This phenomenon, referred to as ischemic preconditioning (PC), has two distinct phases based on the time...

Techniques to Assess Cutaneous Microvascular Function in Vivo

Figure 2 Ions of soluble salt are introduced into the tissue by ion-tophoretic current. The amount of drug delivered to the skin is proportional to the magnitude and duration of the applied current. (see color insert) Techniques to study cutaneous microvascular function will be discussed under three headings techniques to introduce agents into the skin, techniques to assess blood flow and changes occurring therein, and techniques to recover biologically active chemicals from the dermis in order...

Pericyte Density and Its Relationship to Organ Pathology Concluding Remarks

Analogous Phenotypic Consequences of PDGF-B and PDGFRp Mutagenesis Several interesting conclusions may be drawn from comparing the various mouse lines that have been generated by mutagenesis at the PDGF-B or PDGFRb loci. Not surprisingly, perhaps, the range of phenotypes that is seen in the two mutant series is similar. Both the ligand and receptor series display a gradual reduction in pericyte density, and a phenotypic outcome ranging from normal (no phenotype in the unchallenged state) to...

Prevention of Cigarette Smoke Induced Microvascular Dysfunction

Based on the knowledge that we have gained of the path-omechanism of cigarette smoke-induced microvascular dysfunction, we must acknowledge that while some effects may be due to nicotine, many other effects are due to the reactive oxygen species that are either introduced into the organism by the smoke per se, or else released from activated neutrophils, primarily in the lungs of smokers in response to cigarette smoke inhalation. Based on our initial finding that cigarette smoke-induced...

Structural Alterations in Arterioles during Hypertension

In addition to the changes in functional arteriolar control mechanisms in hypertension, structural alterations of arteri-oles and small arteries can contribute to the elevated vascular resistance in this disease. These changes include structural narrowing of the lumen, thickening of the vascular wall leading to an increased wall lumen ratio, and altered mechanical properties of the vessel, such as increased stiffness and reduced distensibility of the vessel wall. These structural alterations of...

Activity and Specificity of Inhibitors of Arachidonic Acid Metabolism

Because cyclooxygenases are the main target of NSAID therapy, the role of cyclooxygenase-derived lipid mediators has been widely studied. Inhibition of cyclooxygenase leads to a decrease in the production of all prostaglandins and thromboxanes, and this accounts for the observed effects of NSAIDs as anti-inflammatory, antipyretic, analgesic, and antithrombotic agents. It also explains their gastrointestinal and renal side effects. Enormous effort has been expended to develop NSAIDs whose...

Section D Blood Thrombosis and Homeostasis

Hemoglobin-Induced Microvascular Dysfunction Review Hemoglobin-Induced Microvascular Dysfunction 629 Problems Encountered with Hemoglobin-based Blood Substitutes during Trials Problems with Hemoglobin-based Blood Substitutes in the Microcirculation Future Possibilities Determinants of Platelet Glycoprotein Ib-IX-V Mediated Microvascular Hemostasis Are They Different from Those Regulating Thrombosis 635 Michael H. Kroll and Shuju Feng Introduction Molecular Effectors of Platelet-Mediated...

Summary and Future Directions

In order to better develop targeted therapies so that they are specific for breast tumors, it is critical to know how the vasculature develops in the normal breast and how it becomes altered to induce hypoxia during breast tumorigen-esis. Further studies that seek to determine the localization and timing of expression of angiogenic factors and their regulators receptors in the epithelium, endothelium, myoepithelium, and stroma should begin to clarify the important mediators of mammary gland...

Applying the Input Output Analogy to Cardiac Microvasculature in Disease

Endothelial cell activation is a term that was originally coined to describe the increased adhesiveness of cultured endothelial cells that had been pretreated with cytokines. The term today may be more broadly defined as the pheno-typic response of the endothelium to an inflammatory stimulus, usually consisting of some combination of procoagulant and proadhesive properties and loss of barrier function. The term endothelial cell dysfunction was and to some extent continues to be used to describe...

Pericyte Pathobiology

The microvessels of the retina are particularly vulnerable to damage induced by diabetes. An early histological sign of diabetic retinopathy is the loss of pericytes. Currently, the mechanisms causing this sight-threatening complication remain uncertain. Recently, Sugiyama and his colleagues proposed that vasoactive molecules, such as extracellular ATP, can become vasotoxic in the diabetic retina. They found that activation of P2X7 purinoceptors not only plays a role in transducing the...

Clinical Features of Hemangioma

What Hemangioma The Fall

Hemangiomas typically appear soon after birth, grow rapidly during the first year of life (proliferating phase), regress slowly from age 1 to 7 (involutingphase), and there after become a fibrofatty residuum (involuted phase). Hence, the life cycle of hemangioma encompasses both proliferation and regression of blood vessels and, as such, presents a unique model system to study the regulation of angiogenesis. The most common form of hemangioma appears within two weeks after birth, yet some...

Permeability Coefficients of Microvessels in Different Tissues and Their Interpretation

Permeability coefficients have been measured in single microvessels mainly in mesentery but also in other tissues including skeletal muscle, brain, lung, and kidney. Estimates of microvascular permeability have also been made for capillary beds in different organs and tissues. Because many millions of capillaries may contribute to net transport here, values are obtained for the products PJS and LPS. The value of S, the area of microvascular wall, may be estimated from the histology of the...

Microvascular Permeability to Solutes

Lipophilic versus Hydrophilic Solutes and the Importance of Flow Limitation The solute permeability (Ps) of the capillary wall is dependent on the oil water partition coefficient, the diffusion coefficient of the solute, Ax, the radius of the solute relative to the pore, and the pore area. Fat-soluble molecules are therefore very permeable across the capillary wall (Ps for oxygen is 1-10 x 10-3cms-1). The concentration gradient across the capillary wall can only be maintained by relatively high...

Physiological Conditions Associated with Stress Failure of Pulmonary Capillaries

The most remarkable physiological situation where stress failure of pulmonary capillaries is seen is in galloping thoroughbred racehorses. There is now evidence that all thoroughbreds in training bleed into their lungs. This condition, called exercise-induced pulmonary hemorrhage, has been known since Elizabethan times, and all sorts of explanations have been offered such as moldy hay. However, recently it has become apparent that exercising thoroughbreds have extremely high pulmonary vascular...

Endothelium Derived Autacoids

The potential role of endothelial cells in flow-dependent dilation gained considerable interest after the pioneering observation by Furchgott and Zawadzki 1 that the endothelium can actively induce changes in vascular tone by the release of a labile relaxing factor. In fact, an obligatory role of endothelial cells in sensing changes in blood flow signals and transducing them into vasodilator responses was demonstrated in large conduit arteries in situ as well as in arteries in vitro....

Subrata Chakrabarti and JZia Ali Khan

1Department of Pathology, University of Western Ontario, London, Canada 2Department of Microbiology and Immunology, University of Western Ontario, London, Canada Diabetes is the leading cause of blindness, renal failure, and limb amputation in the North American population 1, 2 . In spite of improvements in therapeutic modalities, this disorder accounts for significant morbidity and mortality in diabetic patients. Long-standing diabetes leads to structural and functional alterations in both...

Angiogenesis

Angiogenesis (the formation of new vessels from resident capillaries) involves distinct stages matrix degradation, migration, proliferation, and organization of endothelial cells (ECs) into tubes (Figure 1). An increase in vascular permeability is one of the earliest steps in the process. ECs dissociate themselves from surrounding tissue by secreting enzymes that degrade extracellular matrix (basement membrane). Simultaneously, ECs replicate and align themselves into tubules, a process...

Utilization of Window Models

Window models generally allow long-term continuous and or repeated observation and are thus ideal for time-course studies of physiological and pathological events. Window models are best suited for intravital microscopy and are used to study angiogenesis, microcirculation, tumor and engineered tissue growth, disease process, and treatment response. Intravital microscopy is a powerful optical imaging technique that allows noninvasive monitoring of molecular and cellular processes in intact...

Alpha A Fowler III

Division of Pulmonary Disease and Critical Care Medicine, Department of Internal Medicine, Virginia Commonwealth University New technology and specialized medical practices have evolved over the past five decades that permit support of acute and chronic organ failure. The current era in medicine is remarkable for rapid progress in diverse fields such as cancer therapy and transplantation of bone marrow and solid organs. Consequently, patients suffering from diseases that were formerly fatal now...

Arteriolar and Capillary Alterations Associated with IBD

The resting tone of arterioles appears to result from a complex interaction of metabolic, myogenic, neurohumoral, and physical (e.g., stretch or shear) signals received by the Figure 2 All segments of the microcirculation contribute to the pathophysiology of chronic gut inflammation. A variety of inflammatory mediators (e.g., histamine, bradykinin, nitric oxide, prostaglandins) produced by the affected tissue relax the vascular smooth muscle surrounding arterioles. The consequent dilation of...

Signaling by the Tie Receptor Tyrosine Kinases

The Tie family comprises two members Tiel and Tie2. Both of these RTKs are essential for blood vessel formation and maintenance. There have been no ligands yet identified for Tiel, and relatively little is known about the cellular functions and signaling pathways utilized by this receptor. Tiel does inhibit endothelial apoptosis and promote vessel survival. Several ligands, the angiopoietins, have been identified for Tie2. Of these, angiopoietin-l (Angl) and angiopoietin-2 (Ang2) have been best...

Microvascular Responses to Oxidative Stress

Endothelial cells form a single cell layer on the inner surface of all vessels of the cardiovascular system. These cells play a critical role in physiological regulation of the microcirculation as well as in the pathogenesis of microvascular inflammation. It is now recognized that endothelial dysfunction resulting from oxidative stress is an underlying cause of many vascular diseases. In addition, oxidant-induced endothelial dysfunction can impair microvascular function in several ways (Figure...

Regulation of the Structure of Pulmonary Capillaries

It is clear from the above that the blood-gas barrier has a bioengineering dilemma. On the one hand it needs to be extremely thin for adequate gas exchange, but on the other it must be immensely strong to withstand the high mechanical stresses that develop when the capillary pressure rises on exercise, or the lung is expanded to high volumes. We have seen that the human blood-gas barrier maintains its integrity under all but the most exceptional physiological conditions, that is, maximal...

Structure of Microlymphatics

Compared with the high density of the microvasculature, the microlymphatic network is sparse. Individual microlym-phatics originate in the tissue and form bifurcating trees and in some organs, meshworks. Their detailed network morphology depends on the tissue and organ involved. The lymphatics can be divided into two general classes, the initial lymphatics and the contractile lymphatics (Figure 1). Preceding the initial lymphatics there are also prelymphatic channels. We will describe the three...

Pericytes in Vascular Biology A Brief Overview

Retinal capillaries consist of three elementary structures endothelial cells, basement membrane tubes, and intramural pericytes that are located within the basement membrane (Figure 1). Pericytes both in humans and in rodents are present in the retina at an almost 1 1 ratio with endothelial cells. Their high numbers in the retina, even higher than the numbers in the brain, has been associated with the tightness of the blood-retinal barrier. The recruitment of pericytes to the vessel wall has...

Astrocytes

The Role of Astrocytes in the Development of the Blood-Retinal Barrier Recent studies have shown that retinal astrocytes play a significant role in retinal vascular development by angiogenesis and in the induction and maintenance of the blood-retinal barrier (BRB). Glial fibrillary acidic protein (GFAP)-positive astrocytes are found in all vertebrate species that have a retinal vasculature, and the temporal-spatial development of astrocytes precedes the onset of angiogenesis in the retina 2, 5,...

Physiology

Eighty-five percent of the total blood supply to the eye is distributed to the choroid and only 4 percent to the retina. The remaining is distributed to the ciliary body and the iris. The human retinal blood flow has been calculated to be between 35 and 80 mL min. The oxygen extraction for the retinal blood is about 38 percent. In contrast, the oxygen extraction from the uveal blood is very low, with the arteriovenous difference for the choroidal blood about 3 percent. Choroidal blood flow is...

Pathology

The choroidal vasculature is at the heart of age-related macular degeneration. There are many forms of AMD, but the two major types are exudative or wet and nonexudative or dry AMD. In nonexudative AMD eyes, there are macular drusen and sharply defined focal areas of RPE atrophy, which are associated with varying degrees of loss of the choriocapillaris. Drusen is a form of deposit on Bruch's membrane, which is believed to be incompletely digested material from the RPE that cannot traverse...

Section J Inflammation Chapter 106

Free Radicals and Lipid Signaling in Microvascular Endothelial Cells 721 Peter B. Anning and Valerie B. O'Donnell Introduction Prostaglandin H synthases-1 and -2 in ECs Lipoxygenases in ECs CYP Enzymes in ECs Generation of Free Radical Species by PGHS or LOX and CYP Regulation of PGHS, LOX, and CYP by Reactive Oxygen and Nitrogen Species Conclusions Summary Introduction History and Definitions Converting Membrane Components into Signaling Molecules Keeping the Balance Implications for Health...

Microvascular Integrins and Their Extracellular Matrix Ligands

Various genetic data support the notion that the integrin a5b1 and its ECM ligand, fibronectin (FN), are absolutely essential for normal blood vessel function. Mouse embryos harboring an ablated a5 gene die by embryonic day (E) 10.5, displaying severe embryonic and extraembryonic vascular defects, as well as posterior trunk and somitic abnormalities. Additionally, a5-null embryonic stem (ES) cells injected into syngeneic mice form teratocarcinomas with reduced size and a poorly developed...

Sphingosine 1Phosphate S1P

S1P came to prominence a few years after LPA and was found to mimic many of the biologic activities of LPA. A seminal study from the laboratory of Garcia 5 demonstrated that S1P decreases endothelial permeability across cell monolayers derived from bovine and human pulmonary arteries and human umbilical vein. In a number of cell types, S1P appears biologically to be much more potent than LPA. For example, S1P is more active than LPA in human umbilical vein endothelial cells with regard to the...

Microvascular Functional Units

The organization of each liver lobe into structural or functional units related to function and or disease has been the subject of considerable debate during the past century. Several models, none of which are mutually exclusive, have been proposed as follows and as illustrated in Figure 1. The classic hepatic lobule is a polygonal structure having as its central axis a central venule, with portal tracts distributed along its peripheral boundary. The peripheral boundaries of these lobules are...

Mediators of Hepatic Inflammation

When microbes and other inflammatory stimuli first enter the hepatic circulation, they activate sinusoidal endothelial cells and Kupffer cells. These cells then produce a cocktail of proinflammatory mediators such as prostanoids, nitric oxide, cytokines, chemokines, many growth factors, and reactive oxygen species. With the increased expression of these inflammatory mediators comes (1) the recruitment of leukocytes into the inflamed area, (2) the killing of the invading microbes, and in some...

Potential Pathogenic Roles for AECAs

The spectrum of autoantibodies present in patients with autoimmune diseases provides diagnostic utility and must also in principle provide information about the mechanisms underlying the disease process. In several instances, it is also certain that these autoantibodies play a causal role in pathogenesis (e.g., myasthenia gravis, autoimmune thyroid disease). A pathogenic role for AECAs is less certain, and it may well be that in some diseases AECAs arise as the consequence of vascular damage,...

Microvascular Permeability to Water Hydraulic Conductivity Lp

Although cell membranes are freely permeable to the diffusion of water, they have a high resistance to fluid flow down a hydrostatic pressure gradient. Lp is given by the fluid flow per unit pressure per unit area. What Is the Site of the Resistance to Fluid Flow The main pathway of fluid flow across the walls of continuous capillaries is the intercellular cleft, and in fenestrated endothelium through fenestrae. The conductance is determined the viscosity of the fluid (h), the path length (Ax),...

Sirpa Jalkanen and Marko Salmi

University of Turku and National Public Health Institute, Turku, Finland Physiological Lymphocyte Recirculation A subset of vascular endothelial cells in peripheral lymph nodes and in organized lymphatic tissues in the gut (Peyer's patches and appendix) have differentiated to optimally support continuous lymphocyte trafficking into these tissues. They do not mediate extravasation of granulocytes in normal conditions. These vessels are postcapillary venules of the vascular tree and their...

The Basic Concept of Intussusception

Nonsprouting angiogenesis by intussusception was first described in the capillary bed of neonatal rat lungs by Caduff and coworkers 1 . Analyzing scanning electron micrographs of lung vascular corrosion casts, the authors detected a multitude of tiny holes with diameters up to 2 mm. Serial sectioning of lung tissue followed by transmission electron microscopy revealed these structures to correspond to transluminal tissue pillars 1, 2 . Four consecutive steps for pillar formation have been...

Structure and Function of the Cutaneous Microvasculature

The skin is the largest organ in the body. It weighs on average 4 kg and covers an area of approximately 2 m2. The two major functions of the skin are as a barrier protecting the body from the external environment and as a thermoreg-ulatory organ. As a consequence, in addition to providing nutritional support and maintaining tissue homeostasis, the skin microvasculature also plays key roles in immunosur-veillance, hemostasis, and tissue repair and remodeling, as well as in thermoregulation....

Microvasculature and Renal Transplant Rejection

Endothelium of the allograft vasculature is the interface between an allograft and the recipient's immune system. In this boundary position, endothelial cells may play important roles in the afferent and efferent phases of allograft rejection. The expression by endothelial cells of granule membrane protein-140 (GMP-140 P-selectin) and endothelial leukocyte adhesion molecule-1 (ELAM-1 E-Selectin) increases tissue factor activity, augments secretion of plas-minogen activator inhibitor, and...

John F Beltrame

The Queen Elizabeth Hospital, University of Adelaide, Adelaide, Australia The coronary microvasculature plays a fundamental role in the provision and regulation of myocardial perfusion. Accordingly, coronary microvascular dysfunction may frequently contribute to impaired myocardial perfusion and thus play an important role in the genesis of myocardial ischemia. Thus research into coronary microvascular disorders will not only elaborate new conditions and their mechanisms but also provide...

Tissue Distribution of BCRP Compared to Other Multidrug Transporters

The apical siting of BCRP on polarized cells is of particular relevance to the possible role or roles of BCRP in normal tissues. The protein is found in many tissues, including barrier sites, as outlined in Table II. The highest BCRP expression is found in the placenta on the syncytiotrophoblast facing the maternal circulation. This suggests a role for the protein in the elimination of substrates from the fetus. This has been established for mouse Bcrpl in both wild-type and P-gp knockout mice,...

Hemodynamic Aspects of Edema Formation

Approximately one-third of the total body water content is confined to the extracellular space. This compartment is composed of the plasma volume, which under normal circumstances comprises 25 percent of the extracellular space, and the remainder is interstitial fluid. Sodium content governs the total fluid volume in both intravascular and interstitial compartments while plasma proteins (mainly albumin) govern the partitioning between these two compartments. The main regulatory hemodynamic...

Importance of the Arterioles in Hypertension

Arterioles and the small arteries that are located immediately upstream from the arterioles are the major sites of vascular resistance in the peripheral circulation. Thus, changes in the structure and function of these vessels can play a crucial role in the development and maintenance of hypertension, since an elevation in peripheral vascular resistance is a common denominator in virtually all forms of this disease. In addition to controlling the resistance to blood flow in peripheral vascular...

The Role of the Vascular Endothelium in Ebola Pathogenesis

Although we do not yet fully understand why Ebola virus is so potent, the clinical signs and symptoms of human infection with this agent point toward a dysfunction of the vascular system. The syndrome caused by this virus and all HFVs are acute multiorgan diseases, associated with widespread tissue damage and diffuse vascular dysfunction. Macrophages, monocytes, endothelial cells, and hepatocytes are the main cellular targets of the Ebola virus 4 . Macrophages and monocytes are considered the...

Receptor Kinases Regulate Microvascular Growth and Differentiation

One specific area of interest in vascular signal transduc-tion has been the recent identification of receptor tyrosine kinases (RTKs), which coordinate signaling cascades integral to angiogenic phenomena. At least five transmembrane receptor kinases have been shown to possess an expression pattern that is predominantly endothelial, and these can be conceptually subdivided into two groups. One group, or subfamily, encodes the VEGF receptors, flt-1, flk-1, and flt-4, whereas the second group...

Structure and Function of Hepatic Sinusoids

Endothelium Liver

The sinusoids are unique exchange vessels composed of specialized nonparenchymal cells that exhibit structural and functional heterogeneity. The structure of the sinusoid is illustrated in Figure 3. The endothelial cells are highly fenestrated and lack a supporting basal lamina. The fenestrae are organized in clusters known as sieve plates. As a result, there is continuity between the plasma in the sinusoid lumen and the perisinu-soidal space (of Disse). The sinusoidal endothelial cells contain...