Properties of vascular permeability factor in human sera for guinea-pig skin

Summary Properties of vascular permeability factor in native human sera (PF/Nat) showed close similarities with those of necrotizing factor. Time course studies revealed that skin necrosis could be initiated by enhanced vascular permeability.Acknowledgment. The authors wish to thank Prof. H. Hayashi, Kumamoto University for encouragement and discussions.     

Actin dynamics in the regulation of endothelial barrier functions and neutrophil recruitment during endotoxemia and sepsis

Sepsis is a leading cause of death worldwide. Increased vascular permeability is a major hallmark of sepsis. Dynamic alterations in actin fiber formation play an important role in the regulation of endothelial barrier functions and thus vascular permeability. Endothelial integrity requires a delicate balance between the formation of cortical actin filaments that maintain endothelial cell contact stability and the formation of actin stress fibers that generate pulling forces, and thus compromise endothelial cell contact stability. Current research has revealed multiple molecular pathways that regulate actin dynamics and endothelial barrier dysfunction during sepsis. These include intracellular signaling proteins of the small GTPases family (e.g., Rap1, RhoA and Rac1) as well as the molecules that are directly acting on the actomyosin cytoskeleton such as myosin light chain kinase and Rho kinases. Another hallmark of sepsis is an excessive recruitment of neutrophils that also involves changes in the actin cytoskeleton in both endothelial cells and neutrophils. This review focuses on the available evidence about molecules that control actin dynamics and regulate endothelial barrier functions and neutrophil recruitment. We also discuss treatment strategies using pharmaceutical enzyme inhibitors to target excessive vascular permeability and leukocyte recruitment in septic patients.     

Time courses and refractoriness of enhanced vascular permeability induced by histamine,serotonin and bradykinin in synovialis of the rat

Summary Enhanced vascular permeability induced in synovialis of the rat by histamine and serotonin lasts 5–15 min and that induced by bradykinin less than 5 min. Synovialis of the rat becomes refractory to the permeability effects of repeated doses of each of these substances in the hour following initial application.This work was carried out while L.P.B. was supported by a Medical Postgraduate Scholarship from the National Health and Medical Research Council of Australia.     

On the lymphatic spread of cancer

Summary Experimental demonstration that agents promoting cellular motility and/or vascular permeability enhance the spread of tumour to regional or distant lymph nodes. Tumour emboli appear to reach the regional glands via the lymphatic channels and the distant nodes by haematogenous route.     

On the lymphatic spread of cancer

Experimental demonstration that agents promoting cellular motility and/or vascular permeability enhance the spread of tumour to regional or distant lymph nodes. Tumour emboli appear to reach the regional glands via the lymphatic channels and the distant nodes by haematogenous route.     

Microscopical investigations on the 'vessel sealing' effect of calcium ions (author's transl)]

The effect of locally applied calcium on the vascular permeability is studied under the conditions of an acute inflammatory reaction. Using the Sephadex-inflammation, local elevated calcium concentration neither inhibited oedema formation, nor were reduction of inflammatory signs at all observed on the microscopical level.     

Mikroskopische Untersuchungen zur «gefässabdichtenden» Wirkung der Kalziumionen

Summary The effect of locally applied calcium on the vascular permeability is studied under the conditions of an acute inflammatory reaction. Using the Sephadex-inflammation, local elevated calcium concentration neither inhibited oedema formation, nor were reduction of inflammatory signs at all observed on the microscopical level.     

A fast osmotic transition method for the study of pulmonary transcapillary exchange: theoretical model]

A theoretical model allowed the simultaneous determination of the reflexion coefficients of capillary membrane to small hydrophilic molecules and of the ratios of their permeability to filtration coefficient. This was applied to dilution curves obtained after injection of a hypertonic solution containing a vascular tracer. The calculated variables did not depend on the capillary exchange surface area.     

Hageman factor activation and tight junction disruption in mice challenged with attenuated endotoxin.

Endotoxin treated with chromium chloride is less toxic to mice than the parent molecule, but can disrupt intestinal permeability barriers and has an enhanced ability to activate Hageman factor.     

Chronobiological studies on the blood-brain barrier

Summary Horseradish peroxidase (HRP) is a useful tracer for a study of the transportation of exogenous materials across vascular walls. After i.v. administration of HRP, reaction products of HRP can be recognized in the granular perithelial cells of small cerebral blood vessels at particular times of day. It suggests that there is a time-dependent fluctuation in the permeability of small cerebral blood vessels.This paper is dedicated to the late Professor Dr H. v. Mayersbach in Hannover.This study was supported in part by a grant in aid for Scientific Research from the Ministry of Education of Japan (No. 448085).     

RANKL,RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases

1997 saw the identification of a novel set of proteins within the tumor necrosis factor (TNF)/TNF receptor families that are required for the control of bone remodeling. Therefore, these receptors, receptor activator of nuclear factor kappa B (RANK), osteoprotegerin (OPG) and their ligand RANK ligand (RANKL) became the critical molecular triad controlling osteoclastogenesis and pathophysiologic bone remodeling. However, the establishment of the corresponding knock-out and transgenic mice revealed unexpected results, most particularly, the involvement of these factors in the vascular system and immunity. Thus, the OPG/RANK/RANKL molecular triad appears to be associated with vascular calcifications and plays a pivotal function in the development of the immune system through dendritic cells. OPG/RANK/RANKL thus constitute a molecular bridge spanning bone metabolism, vascular biology and immunity. This review summarizes recent knowledge of OPG/RANK/RANKL interactions and activities as well as the current evidence for their participation in osteoimmunology and vascular diseases. In fine, the targeting of the OPG/RANK/RANKL axis as novel therapeutic approaches will be discussed. Received 27 February 2007; accepted 4 April 2007     

Hageman factor activation and tight junction disruption in mice challenged with attenuated endotoxin

Summary Endotoxin treated with chromium chloride is less toxic to mice than the parent molecule, but can disrupt intestinal permeability barriers and has an enhanced ability to activate Hageman factor.We wish to thank Drs M.W. Brightman and T.S. Reese from the Department of Neurocytology, National Institutes of Health for the use of their Balzers freeze-fracture instrument.     

Secretogranin III: a diabetic retinopathy-selective angiogenic factor

Secretogranin III (Scg3) is a member of the granin protein family that regulates the biogenesis of secretory granules. Scg3 was recently discovered as an angiogenic factor, expanding its functional role to extrinsic regulation. Unlike many other known angiogenic factors, the pro-angiogenic actions of Scg3 are restricted to pathological conditions. Among thousands of quantified endothelial ligands, Scg3 has the highest binding activity ratio to diabetic vs. healthy mouse retinas and lowest background binding to normal vessels. In contrast, vascular endothelial growth factor binds to and stimulates angiogenesis of both diabetic and control vasculature. Consistent with its role in pathological angiogenesis, Scg3-neutralizing antibodies alleviate retinal vascular leakage in mouse models of diabetic retinopathy and retinal neovascularization in oxygen-induced retinopathy mice. This review summarizes our current knowledge of Scg3 as a regulatory protein of secretory granules, highlights its new role as a highly disease-selective angiogenic factor, and envisions Scg3 inhibitors as “selective angiogenesis blockers” for targeted therapy.     

Recruitment and retention: factors that affect pericyte migration

Pericytes are critical for vascular morphogenesis and contribute to several pathologies, including cancer development and progression. The mechanisms governing pericyte migration and differentiation are complex and have not been fully established. Current literature suggests that platelet-derived growth factor/platelet-derived growth factor receptor-β, sphingosine 1-phosphate/endothelial differentiation gene-1, angiopoietin-1/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, angiopoietin-2/tyrosine kinase with immunoglobulin-like and EGF-like domains 2, transforming growth factor β/activin receptor-like kinase 1, transforming growth factor β/activin receptor-like kinase 5, Semaphorin-3A/Neuropilin, and matrix metalloproteinase activity regulate the recruitment of pericytes to nascent vessels. Interestingly, many of these pathways are directly affected by secreted protein acidic and rich in cysteine (SPARC). Here, we summarize the function of these factors in pericyte migration and discuss if and how SPARC might influence these activities and thus provide an additional layer of control for the recruitment of vascular support cells. Additionally, the consequences of targeted inhibition of pericytes in tumors and the current understanding of pericyte recruitment in pathological environments are discussed.     

Shear-dependence of endothelial functions

Endothelial cells are subjected to shear forces which influence important cell functions. Shear stress induces cell elongation and formation of stress fibers, increases permeability, pinocytosis and lipoprotein internalization, is involved in the formation of atherosclerotic lesions, increases the production of tissue plasminogen activator, and enhances von Willebrand factor release and hence platelet aggregation. It decreases adherence of erythrocytes and leukocytes, and increases the release of prostacyclin, endothelium derived relaxing factor, histamine and other compounds, but decreases erythropoietin secretion. The mechanism of signal transduction to the endothelial cell is not known exactly; shear-sensitive ion channels seem to be involved. It is concluded that a better understanding of shear-dependent endothelial functions will influence pathophysiologic concepts and therapeutic interventions.     

Vasomotor escape from adrenaline,noradrenaline or acetylcholine in the dog hind limb

Summary The noradrenaline, adrenaline and acetylcholine-induced vasoregulatory escape was demonstrated in the vascular bed of intact or skinned and denervated dog's hind limb. Escape effect disappeared or decreased markedly under elevation tissue pressure in the examined hind limb. These data indicate that tissue pressure factor may take part in the mechanism of the escape phenomenon.     

Formation and role of exosomes in cancer

Exosomes offer new insight into cancer biology with both diagnostic and therapeutic implications. Because of their cell-to-cell communication, exosomes influence tumor progression, metastasis, and therapeutic efficacy. They can be isolated from blood and other bodily fluids to reveal disease processes occurring within the body, including cancerous growth. In addition to being a reservoir of cancer biomarkers, they can be re-engineered to reinstate tumor immunity. Tumor exosomes interact with various cells of the microenvironment to confer tumor-advantageous changes that are responsible for stromal activation, induction of the angiogenic switch, increased vascular permeability, and immune escape. Exosomes also contribute to metastasis by aiding in the epithelial-to-mesenchymal transition and formation of the pre-metastatic niche. Furthermore, exosomes protect tumor cells from the cytotoxic effects of chemotherapy drugs and transfer chemoresistance properties to nearby cells. Thus, exosomes are essential to many lethal elements of cancer and it is important to understand their biogenesis and role in cancer.