The ebb and flow of lymphatic valve formation

Recently, substantial advances have been made in understanding the formation and remodeling of the lymphatic vasculature. In this issue, Sabine et al. (2012) further define the mechanisms of lymphatic valve formation and implicate oscillatory shear stress in regulating the molecular events that control valve morphogenesis.     

The effect of shortening history on isometric and dynamic muscle function

Despite numerous reports on isometric force depression, few reports have quantified force depression during active muscle shortening (dynamic force depression). The purpose of this investigation was to determine the influence of shortening history on isometric force following active shortening, force during isokinetic shortening, and velocity during isotonic shortening. The soleus muscles of four cats were subjected to a series of isokinetic contractions at three shortening velocities and isotonic contractions under three loads. Muscle excursions initiated from three different muscle lengths but terminated at a constant length. Isometric force produced subsequent to active shortening, and force or shortening velocity produced at a specific muscle length during shortening, were compared across all three conditions. Results indicated that shortening history altered isometric force by up to 5%, force during isokinetic shortening up to 30% and shortening velocity during isotonic contractions by up to 63%. Furthermore, there was a load by excursion interaction during isotonic contractions such that excursion had the most influence on shortening velocity when the loads were the greatest. There was not a velocity by excursion interaction during isokinetic contractions. Isokinetic and isotonic power–velocity relationships displayed a downward shift in power as excursions increased. Thus, to discuss force depression based on differences in isometric force subsequent to active shortening may underestimate its importance during dynamic contractions. The presence of dynamic force depression should be realized in sport performance, motor control modeling and when controlling paralyzed limbs through artificial stimulation.     

A fully coupled fluid-structure interaction model of the secondary lymphatic valve

Abstract

The secondary lymphatic valve is a bi-leaflet structure frequent throughout collecting vessels that serves to prevent retrograde flow of lymph. Despite its vital function in lymph flow and apparent importance in disease development, the lymphatic valve and its associated fluid dynamics have been largely understudied. The goal of this work was to construct a physiologically relevant computational model of an idealized rat mesenteric lymphatic valve using fully coupled fluid-structure interactions to investigate the relationship between three-dimensional flow patterns and stress/deformation within the valve leaflets. The minimum valve resistance to flow, which has been shown to be an important parameter in effective lymphatic pumping, was computed as 268?g/mm⁴?s. Hysteretic behavior of the lymphatic valve was confirmed by comparing resistance values for a given transvalvular pressure drop during opening and closing. Furthermore, eddy structures were present within the sinus adjacent to the valve leaflets in what appear to be areas of vortical flow; the eddy structures were characterized by non-zero velocity values (up to ～4?mm/s) in response to an applied unsteady transvalvular pressure. These modeling capabilities present a useful platform for investigating the complex interplay between soft tissue motion and fluid dynamics of lymphatic valves and contribute to the breadth of knowledge regarding the importance of biomechanics in lymphatic system function.     

Visualizing function in the tumor-associated lymphatic system

The recent surge of interest in the lymphatic system can be attributed to two factors: the discovery of cytokines that induce the growth of new lymphatic capillaries and the identification of lymphatic endothelial-specific markers. In contrast to the above, there is a paucity of techniques for studying lymphatic function in vivo. This article reviews imaging and other techniques that allow the assessment of lymphatic function, particularly in the tumor microenvironment, and proposes novel solutions for probing the same in vivo.     

Novel characterization of lymphatic valve formation during corneal inflammation

Lymphatic research has progressed rapidly in recent years. Though lymphatic dysfunction has been found in a wide array of disorders from transplant rejection to cancer metastasis, to date, there is still little effective treatment for lymphatic diseases. The cornea offers an optimal site for lymphatic research due to its accessible location, transparent nature, and lymphatic-free but inducible features. However, it still remains unknown whether lymphatic valves exist in newly formed lymphatic vessels in the cornea, and how this relates to an inflammatory response. In this study, we provide the first evidence showing that lymphatic valves were formed in mouse cornea during suture-induced inflammation with the up-regulation of integrin alpha 9. The number of corneal valves increased with the progression of inflammatory lymphangiogenesis. Moreover, we have detected lymphatic valves at various developmental stages, from incomplete to more developed ones. In addition to defining the average diameter of lymphatic vessels equipped with lymphatic valves, we also report that lymphatic valves were more often located near the branching points. Taken together, these novel findings not only provide new insights into corneal lymphatic formation and maturation, but also identify a new model for future investigation on lymphatic valve formation and possibly therapeutic intervention.     

Functional morphology of the lymphatic system of the rat uterus during pregnancy

In the regional lymph nodes of the uterus the comparative volume of the paracortical zone significantly increases, especially within the period of the 13th-17th days of pregnancy. In the popliteal lymph node similar effect is not discovered. From the 7th up to the 11th day edema, vasodilatation, infiltration with special leucocytes are revealed. Endothelium of the postcapillary venules is hypertrophied, contains many migrating lymphocytes, which accumulate around the vessels mentioned. The volume of the microcirculatory bed is moderately increased. By the 17th day plasmoblasts, plasmocytes, Motta's cells, monocytes and especially macrophages appear in the paracortical zone. In B-zones and in medullary sinuses blasts, plasma cells, monocytes, macrophages, mitotically deviding cells increase in number. The part of the reticular cells decreases. The tensometric method demonstrates an increasing pressure of lymph in the iliac lymph node at pregnancy. Collateralies appear in the ovarian vein system, in the broad ligament of the uterus, in the lumbar area. The uterine vascular system is supposed to participate in adaptation to pregnancy. In genesis of the regional lymph node changes, discirculatory shifts, predominating during placental organogenesis, combine with phenomena of cell migration and proliferation (clearly revealed by the time when formation of the placenta is completed).     

Isolated effect of geometry on mitral valve function for in silico model development

Computational models for the heart's mitral valve (MV) exhibit several uncertainties that may be reduced by further developing these models using ground-truth data-sets. This study generated a ground-truth data-set by quantifying the effects of isolated mitral annular flattening, symmetric annular dilatation, symmetric papillary muscle (PM) displacement and asymmetric PM displacement on leaflet coaptation, mitral regurgitation (MR) and anterior leaflet strain. MVs were mounted in an in vitro left heart simulator and tested under pulsatile haemodynamics. Mitral leaflet coaptation length, coaptation depth, tenting area, MR volume, MR jet direction and anterior leaflet strain in the radial and circumferential directions were successfully quantified at increasing levels of geometric distortion. From these data, increase in the levels of isolated PM displacement resulted in the greatest mean change in coaptation depth (70% increase), tenting area (150% increase) and radial leaflet strain (37% increase) while annular dilatation resulted in the largest mean change in coaptation length (50% decrease) and regurgitation volume (134% increase). Regurgitant jets were centrally located for symmetric annular dilatation and symmetric PM displacement. Asymmetric PM displacement resulted in asymmetrically directed jets. Peak changes in anterior leaflet strain in the circumferential direction were smaller and exhibited non-significant differences across the tested conditions. When used together, this ground-truth data-set may be used to parametrically evaluate and develop modelling assumptions for both the MV leaflets and subvalvular apparatus. This novel data may improve MV computational models and provide a platform for the development of future surgical planning tools.     

Probing the effect of mutations on cytochrome C stability

Although the tertiary structures of mitochondrial cytochromes c (cyts c) seem to be remarkably similar, there are variations in their amino acid sequences, stability and functional properties. GdnHCl-induced unfolding experiments on engineered yeast and horse cyt c were carried out with the aim to to clarify, at molecular level, some aspects concerning the stability of this class of proteins. The results obtained are discussed in the light of the three-dimensional structures of the two proteins.     

The effect of extracellular calcium elevation on morphology and function of isolated rat osteoclasts

Osteoclasts are large multinucleate cells unique in their capacity to resorb bone. These cells are exposed locally to high levels of ionised calcium during the process of resorption. We have therefore examined the effect of elevated extracellular calcium on the morphology and function of freshly disaggregated rat osteoclasts. Cell size and motility were quantitated by time-lapse video recording together with digitisation and computer-centred image analysis. In order to assess the resorptive capacity of isolated osteoclasts, we measured the total area of resorption of devitalised cortical bone by means of scanning electron microscopy and computer-based morphometry. The results show that elevation of the extracellular calcium concentration causes a dramatic reduction of cell size, accompanied by a marked diminution of enzyme release and abolition of bone resorption. We propose that ionised calcium might play an important role in the local regulation of osteoclastic bone resorption.     

Probing the structural basis of RecQ helicase function

RecQ helicases are a ubiquitous family of DNA unwinding enzymes required to preserve genome integrity, thus preventing premature aging and cancer formation. The five human representatives of this family play non-redundant roles in the suppression of genome instability using a combination of enzymatic activities that specifically characterize each member of the family. These enzymes are in fact not only able to catalyze the transient opening of DNA duplexes, as any other conventional helicase, but can also promote annealing of complementary strands, branch migration of Holliday junctions and, in some cases, excision of ssDNA tails. Remarkably, the balance between these different activities seems to be regulated by protein oligomerization. This review illustrates the recent progress made in the definition of the structural determinants that control the different enzymatic activities of RecQ helicases and speculates on the possible mechanisms that RecQ proteins might use to promote their multiple functions.     

Role of adrenoreceptors in the effect of thyroliberin on lymphatic vessels

Formerly we showed that TRH had simulative effect on mesenteric bovine and rat lymphatic vessels (LV) in very low concentration--10(-12)-10(-18) M. In present paper, participation of LV alpha- and beta-receptors in realization of TRH activity on rat mesenteric lymphatic vessels was studied in situ. Propranolol increased the stimulative effect of TRH, isoproterenol exerted an opposite effect. Phentolamine, prazosin eliminated the simulative effect of TRH, yohimbine resulted in additional gain of effect, which seems to testify 1) presynaptic action of TRH or 2) increase of the output of norepinephrine, which is potentiated by alpha 2-adrenoceptor antagonists. Also the participation of adrenergic receptors in positive chronotropic effects of mesenteric rat LV was studied using the method of selective destruction of dopamine-containing neurons after 6-OHDA infusion. As it occurred, desympathization hindered development of stimulating action of TRH. Thus, the efficiency of TRH as a stimulator of LV is connected with activation of adrenergic mechanisms.     

Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1

The hyaluronan receptor LYVE-1 is expressed abundantly on the surfaces of lymphatic vessels and lymph node sinus endothelial cells from early development, where it has been suggested to function both in cell adhesion/transmigration and as a scavenger for hyaluronan turnover. To investigate the physiological role(s) of LYVE-1, we generated mice in which the gene for the receptor was inactivated by replacement with a beta-galactosidase reporter. LYVE-1(-/-) mice displayed an apparently normal phenotype, with no obvious alteration in lymphatic vessel ultrastructure or function and no apparent change in secondary lymphoid tissue structure or cellularity. In addition, the levels of hyaluronan in tissue and blood were unchanged. LYVE-1(-/-) mice also displayed normal trafficking of cutaneous CD11c(+) dendritic cells to draining lymph nodes via afferent lymphatics and normal resolution of oxazolone-induced skin inflammation. Finally, LYVE-1(-/-) mice supported normal growth of transplanted B16F10 melanomas and Lewis lung carcinomas. These results indicate that LYVE-1 is not obligatory for normal lymphatic development and function and suggest either the existence of compensatory receptors or a role more specific than that previously envisaged.