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In the adult bone marrow (BM), endothelial cells (ECs) are an integral component of the hematopoietic stem cell (HSC)-supportive niche, which modulates HSC activity by producing secreted and membrane-bound paracrine signals. Within the BM, distinct vascular arteriole, transitional, and sinusoidal EC subtypes display unique paracrine expression profiles and create anatomically-discrete microenvironments. However, the relative contributions of vascular endothelial subtypes in supporting hematopoiesis is unclear. Moreover, constitutive expression and off-target activity of currently available endothelial-specific and endothelial-subtype-specific murine cre lines potentially confound data analysis and interpretation. To address this, we describe two tamoxifen-inducible cre-expressing lines, Vegfr3-creERT2 and Cx40-creERT2, that efficiently label sinusoidal/transitional and arteriole endothelium respectively in adult marrow, without off-target activity in hematopoietic or perivascular cells. Utilizing an established mouse model in which cre-dependent recombination constitutively-activates MAPK signaling within adult endothelium, we identify arteriole ECs as the driver of MAPK-mediated hematopoietic dysfunction. These results define complementary tamoxifen-inducible creERT2-expressing mouse lines that label functionally-discrete and non-overlapping sinusoidal/transitional and arteriole EC populations in the adult BM, providing a robust toolset to investigate the differential contributions of vascular subtypes in maintaining hematopoietic homeostasis. [ABSTRACT FROM AUTHOR]

Hematopoietic stem cells (HSCs) exist in a close contact with their specific microenvironment, called a niche, which supports the HSC function and significantly influences the HSC properties. The existence of the HSC niche, which was proposed as a purely theoretical concept in 1978, finds increasing experimental evidence and is now generally accepted by specialists in the field of hematopoiesis. The review briefly describes various cell components of the HSC niche in bone marrow, considers the metabolic states of the niche and HSCs, and discusses other aspects of niche biology. Increasing knowledge of the HSC niche will help to create in vitro cell models of the HSC niche, to modulate the HSC properties, and to achieve multifold HSC expansion in culture for further applications in therapeutic practice. [ABSTRACT FROM AUTHOR]

Hepatic sinusoidal dilatation refers to the enlargement of the hepatic capillaries. Most of the time this condition is caused by hepatic venous outflow obstruction, which results in vascular stasis and congestion of hepatic parenchyma. In this setting, hepatic sinusoidal dilatation can be related to pericardial disease, heart failure, compression or thrombosis of the hepatic veins or inferior vena cava (i.e., Budd-Chiari syndrome) or central veins/sinusoids involvement (i.e., sinusoidal obstruction syndrome). Nevertheless, some extrahepatic inflammatory conditions (such as pyelonephritis, cholecystitis, pneumonia, pancreatitis, intestinal bowel disease, and others) may be associated with hepatic sinusoidal dilatation without concurrent venous outflow obstruction. On contrast-enhanced cross-sectional imaging, hepatic sinusoidal dilatation is typically characterized by a mottled, reticular enhancement of the liver, usually referred to as “mosaic” pattern. Other hepatic and extrahepatic imaging features, such us the dilatation of the hepatic veins or the presence of ascites, can help in identifying the cause of sinusoidal dilatation. [ABSTRACT FROM AUTHOR]

Intratumor hemorrhage is a poor prognostic factor in pineal choriocarcinoma (PCCC). The aim of this study was to understand the relationship of tumor cells to the blood vessels to gain insights into the formation of intratumor hemorrhage in PCCC. The clinical data indicated that total tumor removal by surgical procedures followed immediately by radiotherapy and chemotherapy improved the prognosis in PCCC. The PCCC tissues removed from the patients were examined by histology and immunohistochemistry. Hematoxylin and eosin staining showed that the tumor stroma mainly consists of hemorrhagic tissues with tumor cells scattered inside. The pattern of distribution suggests that the tumor cells were possibly flushed and compressed by the bleeding. The tumor cells tended to form sinusoids that lacked CD34, but laminin expression provided evidence of vasculogenic mimicry. Interestingly, CD34-positive blood vessels were found connected to these sinusoids, suggesting that blood may flow from the tumor vasculature to the sinusoids. This may subsequently cause the enlargement of the sinusoids, blood clotting, the widening of the blood lakes, and eventually extensive hemorrhagic necrosis. Our study identified the key features of the PCCC vasculature. The findings add to the previous understanding of the formation of vascular channels, blood lakes, and extensive hemorrhagic necrosis. The intimate connections between the tumor-formed sinusoids and the blood vessels might be a major cause of severe hemorrhage in PCCC. The new information may be useful for the development of treatment strategies for managing PCCC. [ABSTRACT FROM AUTHOR]

Sinusoids are specialized, low pressure blood vessels in the liver, bone marrow, and spleen required for definitive hematopoiesis. Unlike other blood endothelial cells (ECs), sinusoidal ECs express high levels of VEGFR3. VEGFR3 and its ligand VEGF-C are known to support lymphatic growth, but their function in sinusoidal vessels is unknown. In this study, we define a reciprocal VEGF-C/VEGFR3-CDH5 (VE-cadherin) signaling axis that controls growth of both sinusoidal and lymphatic vessels. Loss of VEGF-C or VEGFR3 resulted in cutaneous edema, reduced fetal liver size, and bloodless bone marrow due to impaired lymphatic and sinusoidal vessel growth. Mice with membrane-retained VE-cadherin conferred identical lymphatic and sinusoidal defects, suggesting that VE-cadherin opposes VEGF-C/VEGFR3 signaling. In developing mice, loss of VE-cadherin rescued defects in sinusoidal and lymphatic growth caused by loss of VEGFR3 but not loss of VEGF-C, findings explained by potentiated VEGF-C/VEGFR2 signaling in VEGFR3-deficient lymphatic ECs. Mechanistically, VEGF-C/VEGFR3 signaling induces VE-cadherin endocytosis and loss of function via SRC-mediated phosphorylation, while VE-cadherin prevents VEGFR3 endocytosis required for optimal receptor signaling. These findings establish an essential role for VEGF-C/VEGFR3 signaling during sinusoidal vascular growth, identify VE-cadherin as a powerful negative regulator of VEGF-C signaling that acts through both VEGFR3 and VEGFR2 receptors, and suggest that negative regulation of VE-cadherin is required for effective VEGF-C/VEGFR3 signaling during growth of sinusoidal and lymphatic vessels. Manipulation of this reciprocal negative regulatory mechanism, e.g. by reducing VE-cadherin function, may be used to stimulate therapeutic sinusoidal or lymphatic vessel growth., Competing Interests: Competing interests: The authors declare no competing financial interests.

LYVE-1, a specific marker of lymphatics, is expressed in hepatic sinusoidal endothelium. A previous study revealed that LYVE-1 expression in sinusoidal endothelium was reduced in cirrhosis. However, it is still obscure how LYVE-1 expression in sinusoidal endothelium was reduced during the disease progression. To elucidate whether there were relationships among LYVE-1 attenuation, sinusoidal capillarization, and disease progression, we performed immunohistochemical investigations based on frozen human livers. Frozen liver sections of chronic hepatitis ( n = 8), cirrhosis ( n = 13), and normal/control liver ( n = 10) were examined by immunostaining for lymphatic endothelial markers (LYVE-1 and D2-40) and vascular endothelial markers (CD31 and von Willebrand factor). Computer-aided morphometry was applied to obtain objective data. The diseased liver tissues were also examined ultrastructurally. In controls, sinusoidal endothelium was positive for LYVE-1 and CD31, but negative for D2-40 and von Willebrand factor. In chronic hepatitis and cirrhosis, LYVE-1 expression in sinusoidal endothelium was attenuated, especially in areas adjacent to active inflammatory or fibrotic lesions, while von Willebrand factor was reciprocally expressed in sinusoidal endothelium. The morphometric analyses revealed that LYVE-1 positivity in sinusoidal endothelium was significantly ( P < 0.0001) decreased in chronic hepatitis and cirrhosis compared to controls and was negatively correlated (Rs = −0.72, P < 0.0001) to von Willebrand factor positivity. Furthermore, LYVE-1 positivity was negatively correlated to inflammatory grade (Rs = −0.51, P = 0.021) and fibrosis severity (Rs = −0.46, P = 0.038). Sinusoidal endothelium in the diseased livers showing LYVE-1 attenuation had lost fenestrations. These findings indicated that LYVE-1 attenuation in sinusoidal endothelium was one of the manifestations of capillarization, and was associated with hepatic disease progression. [ABSTRACT FROM AUTHOR]

Hepatic blood vessels consist of the hepatic artery and three types of venous channels (the portal veins, the sinusoids, and the hepatic veins). This study was undertaken to analyze, by immunohistochemistry, connexin expression throughout the vascular development of the fetal mouse liver with special attention being given to portal vein development. In the adult liver, connexin37 and connexin40 were expressed in the endothelium of the portal vein and hepatic artery, but not in those of the hepatic vein and sinusoids. Connexin43 was expressed in mesothelial cells and smooth muscle cells of the portal veins. The preferential expression of connexin37 and connexin40 in portal veins was seen throughout liver development, including its primordium formation stage (10.5-day or 11.5-day stage), although connexin37 expression was transiently seen in free nonparenchymal cells in fetal stages. The differentiation of each blood vessel in the hepatic vascular system may occur in early developmental stages, soon after hepatic primordium formation. [ABSTRACT FROM AUTHOR]

Purpose: The disintegration of heme produces carbon monoxide (CO), a known vasodilator, which is catalyzed by heme oxygenase (HO). This study aimed to clarify the effect of HO inhibition on septicrat livers using two types of HO inhibitors; Sn-protoporphyrin (Sn-PP) and Zn-protoporphyrin (Zn-PP). Methods: Sepsis was induced in male Sprague-Dawley rats by cecal ligation and puncture (CLP). Either NaOH or HO inhibitors were injected intraperitoneally; first 18 h prior to CLP, then immediately after CLP. The animals were killed 12 and 24 h after CLP and the liver tissue and plasma were harvested. Results: Using Northern blotting, we found that mRNA of the stress-inducible isozyme, HO-1, was dramatically induced 12 h after CLP. Administering the HO inhibitors, Sn-PP and Zn-PP (5 μmol/kg), induced a significant inhibition of the elevation of aspartate aminotransferase plasma levels, the elevation of cyclic guanosine monophosphete (cGMP) in the liver tissue, and the increase in the sinusoidal space ratio, 24 h after CLP. Both Sn-PP and Zn-PP decreased the mortality rate 24 h after CLP compared with normal saline. Conclusions: CO produced by excessively induced HO-1 after CLP promotes an immoderate dilation of the sinusoidal space through the up-regulation of cGMP, resulting in liver dysfunction. Therefore, administering HO inhibitors at appropriate doses could be beneficial for the amelioration of sepsis-induced liver dysfunction. [ABSTRACT FROM AUTHOR]

We examined the effect of steroid treatment on the intraosseous femoral vasculature in rabbits, with particular emphasis on the morphologic changes in bone marrow sinusoids and central veins. Adult rabbits were divided into three treatment groups: group A, untreated control; group B, animals were treated with intramuscular injections of methylprednisolone acetate (4 mg/kg/week) for 4 weeks; and group C, rabbits which received injections for 8 weeks. Examination of the intraosseous femoral vasculature was performed using microangiography, scanning electron micrography using a corrosion cast method, and retrograde venography. Bone marrow sinusoids of group C were dilated and the network of anastomosed vessels was irregular compared with those of group A. Changes in group B were intermediate between the control rabbits and group C. Retrograde venography of the central vein showed an irregular course and frequent narrowing of the signal. There were no arterial changes in the steroid-treated groups. These findings indicate that steroid therapy does not induce arterial ischemia but rather intraosseous venous stasis extending from bone marrow sinusoids to the central veins. These changes are attributable to bulging or dilatation of sinusoids, a rise in intraosseous pressure, and reduced blood flow. [ABSTRACT FROM AUTHOR]

Common variogram models, such as spherical or exponential functions, increase monotonically with increasing lag distance. On the other hand, a hole-effect variogram typically exhibits sinusoidal waves that form peaks and troughs, thereby conveying the cyclicity of the underlying phenomenon. In order to incorporate this cyclicity into a stochastic simulation, hole effects in the experimental variogram must be fitted appropriately. In this paper, we recommend use of several multiplicative-composite variogram models to fit hole-effect experimental variograms. These consist of a cosine function to provide wavelength and phase of cyclicity, multiplied by a monotonic model (e.g., spherical) to attenuate amplitudes of the cyclical peaks and troughs. These composite models can successfully fit experimental lithology-indicator variograms that contain a range of cyclicities, although experimental variograms with poor cyclicity require special considerations. [ABSTRACT FROM AUTHOR]

The surface ultrastructure of Kupffer cells in the rat liver has been studied by scanning electron microscopy (SEM). The results demonstrate that Kupffer cells are both significantly different and clearly distinct from endothelial cells. Kupffer cells have neither pores (and/or 'sieve plates') nor fenestrations, all of which are present in endothelial cells. They possess a stellate shape, and only indirectly, with slender and irregular evaginations, contribute to the lining of the sinusoidal wall. Furthermore, the luminal surface in some areas contains a large population of short microvilli, microplicae and invaginations. These elements form a kind of microlabyrinth which may correspond to the 'worm-like' structures described by transmission electron microscopy (TEM). In the present study, transition forms between endothelial and Kupffer cells were never found. On the contrary, considering the highly fenestrated nature of the endothelial cells, the Kupffer cells may, by ameboid movements, easily cross the overlapping barrier of the sinusoid and protrude into the lumen. Thus, acting as activated macrophages, the Kupffer cells might function to prevent the entrance of foreign material into the tissues of the liver through the fragile and highly fenestrated endothelium. Finally, the topographical reconstruction of the sinusoid by correlated SEM and TEM studies demonstrates that Kupffer cells, with their protruding cytoplasm and ability to extend into the lumen of the sinusoid, may actually change the caliber of the vessel, and thus function as a 'sphincter' which causes a temporary arrest of the blood flow when the diameter of the sinusoidal lumen is reduced. [ABSTRACT FROM AUTHOR]

The fine structure and functional properties of Kupffer's stellate cells and endothelial cells of the hepatic sinusoid of normal and experimental rabbits were studied using light as well as electron microscopy. [ABSTRACT FROM AUTHOR]

Fine structural alterations of liver sinusoids in young and adult albino rats breathing 6% oxygen in nitrogen at normal atmospheric pressure for periods from 3 to 30 h were described by use of TEM and SEM. After short-term hypoxia the fenestrated areas of endothelial cells were partially destroyed. After long-term hypoxia wide gaps could be visualized in the endothelium, too. In the liver specimens of all hypoxic animals electron lucent membrane bounded blebs arose from the endothelial lining. Cytoplasmic protrusions of hepatocytes bulged into the sinusoidal lumen. In the space of Disse and the sinusoidal lumen bleblike corpuscles and parts of cytoplasmic membrane being discharged from liver cell vacuoles could be observed. The fine structure of liver sinusoids in hypoxia was very similar in young and adult albino rats. The findings suggest a discharge of metabolites and cellular components from endothelial cells and hepatocytes in a state of energetic insufficiency by forming cellular blebs and protrusions. It was supposed, that the combined effects of hypoxia and shearing of circulating blood were responsible for the development of holes and gaps in the endothelial lining. Mit dem TEM und REM wurden die feinstrukturellen Veränderungen der Lebersinusoide von jungen und ausgewachsenen Albinoratten nach 3, 6 und 30stündiger respiratorischer Hypoxie untersucht. Nach 3stündiger Hypoxie fanden sich Defekte in den fenestrierten Anteilen der Endo-thelzellen, nach 6 und 30stündiger Hypoxie waren zusätzlich größere Lücken im Endothel-zellverband nachweisbar. In allen Versuchsgruppen wurden blasige Abschnürungen an den Endothelzellen beobachtet. Vereinzelt fanden sich plumpe Cytoplasmaprotrusionen der Leber-parenchymzellen in die Sinuslichtung, häufig wurden aus Leberzellvakuolen blasige Gebilde und Membrananteile in die Sinusoide abgegeben. Das morphologische Bild der Lebersinusoide bei Hypoxie war bei jungen und ausgewachsenen Ratten weitgehend gleich. Die Befunde lassen vermuten, daß die energetisch insuffizienten Endothelzellen und Hepatocyten Stoffwechselprodukte und Zellmaterial in Form von blasigen Abschnürungen abgeben. Als Ursache der Defekte in den Endothelzellen wird das Zusammenwirken von Sauerstoffmangel und Strömungskräften des Blutes angenommen. [ABSTRACT FROM AUTHOR]

Pit cells - a new type of cell first described here and so named because they contain highly characteristic granules - are situated in the wall of rat liver sinusoids, and have hyaloplasmic pseudopodia intermingling with the microvilli of the parenchymal cells. The characteristic granules are mainly situated at one side of the nucleus, the other side showing organelle-free hyaloplasm. Pit cells are also found in portal tracts and in granuloma-like cellular aggregates. They also occur in rat peripheral blood, although there are morphological differences between cells in these two sites. Pit cells can be regarded as regular inhabitants of the sinusoidal wall, and therefore belong to the series of sinusoidal cells, i.e., the endothelial (Wisse, 1972), Kupffer (Widmann et al., 1972; Wisse and Daems, 1970; Wisse, 1974a,b), and fat-storing cells (Ito, 1973). Pit cells do not phagocytose and do not react to a great number of experimental conditions, to which endothelial and Kupffer cells do react (Wisse, 1972, 1974b). Mitosis has been observed in a pit cell. The function of pit cells remains obscure, but an endocrine function is suggested by the morphology of their highly characteristic granules. [ABSTRACT FROM AUTHOR]

Extracellular recordings were made in the lateral and inferior vestibular nuclei of decerebrate, unanesthetized cats. The firing patterns of single units were studied using small amplitude sinusoidal roll tilts of from 0.01 Hz to 1.0 Hz. Three-fourths of the tilt-sensitive units showed greater modulation of their firing rates as the frequency of the sinusoidal tilt was increased. The responses of cells in both nuclei were similar. These responses were virtually unchanged in cats with chronically plugged semicircular canals, indicating a probable otolith origin for the dynamics of the tilt response. [ABSTRACT FROM AUTHOR]