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The existence of lymphatic vessels in dental pulp has been a matter of continuing controversy because of the difficulty of discriminating them in ordinary stained tissue sections. Recently, we have succeeded in establishing a new identification method for lymphatic vessels in human frozen sections by using a commercial monoclonal antibody specific for the human thoracic duct and anti-human laminin antiserum. The present study aimed to examine the lymphatic vessels in human dental pulp using the new immunostaining method, and compared the results with those in human small intestine. The study clearly demonstrated the distribution of lymphatic vessels in human dental pulp. Large lymphatic vessels are located in the central part of the pulp and there are small lymphatic vessels in the periphery of the pulp. This suggests that lymphatic drainage of the human dental pulp starts from the periphery of the pulp and collects in the central part of the pulp. A notable difference between the small intestine and dental pulp was found in the immunoreactivity of lymphatic vessels to anti-human laminin anti-serum. In small intestine, immunoreactivity was significantly weaker than that of the blood vessels, whereas in dental pulp, that of lymphatic vessels was almost the same as blood vessels, except for some lymphatic vessels showing very weak reactivity. These findings suggest that the development of the basement membrane in both the lymphatic and blood vessels of human dental pulp is not as marked as in other tissue.
The lymphatic vascular system plays a pivotal role in mediating tissue fluid homeostasis and cancer metastasis, but the molecular mechanisms that regulate its formation and function remain poorly characterized. A comparative analysis of the gene expression of purified lymphatic endothelial cells (LEC) versus blood vascular endothelial cells (BVEC) revealed that LEC express significantly higher levels of hepatocyte growth factor receptor (HGF-R). Whereas little or no HGF-R expression was detected by lymphatic vessels of normal tissues, HGF-R was strongly expressed by regenerating lymphatic endothelium during tissue repair and by activated lymphatic vessels in inflamed skin. Treatment of cultured LEC with HGF promoted LEC proliferation, migration and tube formation. HGF-induced proliferation of LEC did not require vascular endothelial growth factor receptor-3 activation, and HGF-induced cell migration was partially mediated via integrin alpha-9. Transgenic or subcutaneous delivery of HGF promoted lymphatic vessel formation in mice, whereas systemic blockade of HGF-R inhibited lymphatic function. These results identify HGF as a novel, potent lymphangiogenesis factor, and also indicate that HGF-R might serve as a new target for inhibiting pathological lymphangiogenesis.
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The lymphatic system is generally regarded as supplementary to the blood vascular system, in that it transports interstitial fluid, macromolecules, and immune cells back into the blood. However, in insects, the open hemolymphatic (or lymphohematic) system ensures the circulation of immune cells and interstitial fluid through the body. The Drosophila homolog of the mammalian vascular endothelial growth factor receptor (VEGFR) gene family is expressed in hemocytes, suggesting a close relationship to the endothelium that develops later in phylogeny. Lymph hearts are typical organs for the propulsion of lymph in lower vertebrates and are still transiently present in birds. The lymphatic endothelial marker VEGFR-3 is transiently expressed in embryonic blood vessels and is crucial for their development. We therefore regard the question of whether the blood vascular system or the lymphatic system is primary or secondary as open. Future molecular comparisons should be performed without any bias based on the current prevalence of the blood vascular system over the lymphatic system. Here, we give an overview of the structure, function, and development of the lymphatics, with special emphasis on the recently discovered lymphangiogenic growth factors.
BACKGROUND: The lymphatic endothelial hyaluronan receptor (LYVE-1) is a specific cell surface protein in lymphatic endothelium. The antiserum against human LYVE-1 was developed and was confirmed a powerful marker of lymphatic endothelium in human organs. With this novel marker we investigated the small network of intraprostate lymphatic vessels. METHODS: To identify intraprostatic lymphatic vessels, we performed an immunohistochemical staining method using LYVE-1 pAb and von Willebrand Factor (vWF), and assessed the difference in distribution of small lymphatic vessels between the components in the prostate. RESULTS: The density of lymphatic vessel was significantly high around ejaculatory ducts and in the fibromascular area between the globular area of peripheral zone and transitional zone. Predominat lymphatic vessels distributed in the fibromascular area in the anterior and posterior prostate of extrastromal area. CONCLUSIONS: Recognition of the distinctive features of the intraprostate lymphatic network, can help the investigation of lymphatic involvement in cancer of the prostate.
Lymphatic metastasis to the regional lymph nodes through the lymphatic vessels is an important indicator of poor prognosis in many types of malignant tumors. Recently, much attention has been paid to lymphangiogenesis for its possible role on tumor progression in various carcinomas. However, morphological evidence that lymphatic vessels actively proliferate in colorectal carcinoma has not been reported. Here, we first devised a triple immunostaining method to detect proliferating lymphatic vessels utilizing antibody to Ki-67 antigen as a marker of cell proliferation, antibody to cytokeratin as an epithelial cell marker, and antibody to podoplanin as a lymphatic vessel-specific marker. Ki-67/podoplanin-immunoreactivity enabled us to identify proliferating lymphatic vessels, while cytokeratin immunoreactivity allowed us to distinguish proliferating lymphatic vessels from Ki-67/cytokeratin-positive carcinoma cells in lymphatic lumens. Analyzing 64 colorectal carcinoma patients' samples using this technique, we showed that both lymphatic vessel density and proliferating activity of lymphatic vessels were significantly increased in colorectal carcinoma tissues compared with their normal counterparts. We then examined the correlation between the degree of lymphangiogenesis and patients' prognosis or clinicopathological variables, but no statistically significant differences were obtained in these analyses. Thus, these results combined together indicate that extensive lymphangiogenesis occurs in colorectal carcinoma, but that the degree of lymphangiogenesis alone is not an independent prognostic factor for this disease.
The afferent lymphatic vessels of rat popliteal lymph nodes were interrupted, and the histological alterations in the lymph nodes occurring 1 to 14 weeks after operation were studied. One week after operation the number of macrophages was considerably reduced and continued to decrease during the subsequent time periods studied. At 6 weeks most macrophages had disappeared. Simultaneously the immunological activity diminished and had completely disappeared 8 weeks after operation. Three weeks after operation the endothelial cells of the postcapillary high endothelial venules had flattened, and the number of immigrating lymphocytes was greatly reduced. Subsequently the lymph nodes became depleted of both macrophages and lymphocytes, leaving only the reticuloendothelial framework.
Edema occurs in asthma and other inflammatory diseases when the rate of plasma leakage from blood vessels exceeds the drainage through lymphatic vessels and other routes. It is unclear to what extent lymphatic vessels grow to compensate for increased leakage during inflammation and what drives the lymphangiogenesis that does occur. We addressed these issues in mouse models of (a) chronic respiratory tract infection with Mycoplasma pulmonis and (b) adenoviral transduction of airway epithelium with VEGF family growth factors. Blood vessel remodeling and lymphangiogenesis were both robust in infected airways. Inhibition of VEGFR-3 signaling completely prevented the growth of lymphatic vessels but not blood vessels. Lack of lymphatic growth exaggerated mucosal edema and reduced the hypertrophy of draining lymph nodes. Airway dendritic cells, macrophages, neutrophils, and epithelial cells expressed the VEGFR-3 ligands VEGF-C or VEGF-D. Adenoviral delivery of either VEGF-C or VEGF-D evoked lymphangiogenesis without angiogenesis, whereas adenoviral VEGF had the opposite effect. After antibiotic treatment of the infection, inflammation and remodeling of blood vessels quickly subsided, but lymphatic vessels persisted. Together, these findings suggest that when lymphangiogenesis is impaired, airway inflammation may lead to bronchial lymphedema and exaggerated airflow obstruction. Correction of defective lymphangiogenesis may benefit the treatment of asthma and other inflammatory airway diseases.
Intralobular lymphatic vessels in the mouse thymus were demonstrated enzyme-histochemically by combined light and electron microscopy. In sections reacting to both 5'-nucleotidase (5'-Nase) and alkaline phosphatase (ALPase), the intralobular lymphatic vessels were identified as irregularly shaped spaces with strong 5'-Nase activity. The lymphatic vessels were closely associated with the branches of ALPase-positive intralobular arteries and veins. The initial lymphatics, which presumably originate from the perivascular spaces, were 5'-Nase positive. The distribution and intensity of the 5'-Nase activity in the lymphatic vessels revealed by light microscopy correlated well with those by backscattered image electron microscopy. The backscattered image scanning electron microscopy of the same area as observed under a light microscope more clearly highlighted the peculiar contours of lymphatic endothelial cells. Transmission electron microscopy showed that specific reaction product of the 5'-Nase after incubation in a medium containing L-tetramisole was predominantly localized on the outer surface of the lymphatic endothelial cell membranes.
In the absence of antibodies specific for lymphatic vessels, analysis of lymphatic vessels within different tissues has been widely performed with light microscopic and, most importantly, electron microscopic techniques. In regard to lymphatic vessels in the ocular globe and the periocular structures, controversy remains about the specific distribution of lymphatic channels. It is postulated that bulbar and retrobulbar tissues are devoid of lymphatic vessels, but lymphatic vessels have been demonstrated in lacrimal gland and epibulbar conjunctiva. In this study, we analyzed orbital fat for the presence of lymphatic tissue using D2-40, a monoclonal antibody, specific for lymphatic vessels. We found lymphatic vessels present within bulbar conjunctiva extending to the level of the ciliary apparatus. No lymphatics were identified in healthy anterior orbital adipose tissue. In two cases of orbital mucor-mycosis and one case of panendophthalmitis, significant lymphovascular proliferation was present within granulation tissue associated with the acute inflammation. We conclude that lymph vessel proliferation may be induced in inflammatory conditions in tissues which are normally devoid of lymph channels.
OBJECTIVE: To study the relationship between density, location, proliferation of lymph vessels and clinicopathological features of laryngeal squamous carcinoma. METHOD: Tumor lymph vessels were quantitated and located in archival specimens of laryngeal carcinoma by LSAB immunostaining for the recently described lymphatic endothelial marker LYVE-1. The Ki67 proliferation marker was used to evaluate the proliferating conditions of LYVE-1(+) vessels with EnVision immunohistochemical methods. RESULT: (1) The density of intratumoral LYVE-1(+) vessels was higher in the cases of neck lymph nodal metastasis group than that of no neck lymph nodal metastasis group (P = 0.000). There was a significant difference of the density of intratumoral LYVE-1(+) vessels in the cases of T1, T2 and T(3-4) group. There was no significant difference of the density of intratumoral LYVE-1(+) vessels between supraglottic group and glottic group, squamous cell histological types I group and types II group (P = 0.125, 0.146, respectively). (2) The density of peritumoral LYVE-1(+) vessels was higher in the cases of neck lymph nodal metastasis group than that of no neck lymph nodal metastasis group. However,there was no statistic significance (P = 0.253). (3) Ki67(+) immunostaining occurs in some of the intratumoral LYVE-1(+) vessels, interestingly, there was no this phenomenon in the peritumoral LYVE-1(+) vessels. CONCLUSION: Intratumoral lymph vessel density marked by LYVE-1 in laryngeal carcinoma was significantly correlated with tumor infiltration and metastasis. Our results provide potent evidence that proliferating lymphatics exists in intratumoral areas of laryngeal carcinoma mainly which maybe contribute to lymph node metastasis in some cases.
Lymphatic vessels are believed to be distributed in the the depth of synovial membrane, but the details of this distribution remain to be fully elucidated. The synovial membrane is classified in part on the basis of histological characteristics, even in the same joint capsule, into three fundamental types: adipose type, areolar type, and fibrous type. In addition, the adipose and areolar types are involved in the absorption of synovial fluid. In this study, the distribution of lymphatic vessels was investigated with special reference to histological structure of the synovial membrane. The materials were prepared from 11 elbow joint capsules of male 8 rabbits weighting 2-3 kg. Five specimens were stained with silver nitrate, and the remainder were stained with trichrome. All of the materials were serially sectioned and observed by light microscopy. Three-dimensional reconstructions of lymphatic vessels were performed using Cosmozone 2SA software (Nikon Co.) with a PC-9800 series microcomputer (NEC Co.) When the joint capsule is divided into synovial and fibrous layers in accordance with the Nomina Histologica Japonica, the fibrous layer is frequently connected with the epimysium of neighboring muscles. The synovial and fibrous layers are occasionally continuous with each other, without a distinct boundary. The number of lymphatic vessels in the synovial layer is small, and they originate in the vicinity of the border of the fibrous layer and pass over into the lymphatic vessels of the fibrous layer. Many lymphatic vessels were found in the fibrous layer, the majority of which come from the epimysium or perimysium close to the outer surface of the fibrous layer.(ABSTRACT TRUNCATED AT 250 WORDS)
Lymphatic vessels were few in the edematous portion of the cholesteatoma perimatrix of the human middle ear. But the lymphatic vessels contained mucus and consisted of degenerated endothelial cells. Edema of the perimatrix was considered to be caused by the degeneration of lymphatic vessels. Normal lymphatic vessels were found in the fibrous perimatrix, while macrophages infiltrated and phagocytosed cell debris. In addition, regenerating blood vessels were observed. Degeneration of connective tissue due to lymphatic edema and its repair were both present in the perimatrix. The degeneration of perimatrix was hypothesized to be caused by confined mucous epithelium behind the cholesteatoma matrix.
The distribution of elastin-like immunoreactivity around small lymphatic vessels was investigated in three different human tissues (skin, heart and dental pulp) using high resolution immunocytochemistry. Quantitative assessment of the immunogold reaction was performed with an image analysis system. Intense and moderate elastin-immuno-reactivity was detected in the extracellular matrix around small lymphatic vessels of the skin and heart, respectively. By contrast, absence of immunostaining was observed around lymphatic vessels in the dental pulp. Although the staining was mostly detectable on the non-fibrillar amorphous component of the extracellular matrix, some microfibrils were also immunostained in close proximity to the lymphatic vessel wall. These findings support the concept that small lymphatic vessels may be heterogeneous with respect to the composition of the extracellular matrix around their wall. The observation that it is possible to observe small lymphatic vessels displaying low or no elastin-immunoreactivity in the adjoining matrix militates against the hypothesis that elastic fibers play a pivotal role in the mechanisms that regulate the function of small lymphatic vessels.
Morphological alterations in venous and lymphatic vessels were studied on 38 dogs over time after ligation of the main veins of the hind limb and induction of experimental chronic venous failure. Under these conditions the operated limb developed marked lymphovenous congestion with ectasis and dilatation of blood and lymphatic vessels and capillaries, venous and lymphatic vessels of the limb followed by an increase in the number of the vessels due to high blood content of "reserve" capillaries and small veins in the presence of acute tissue edema. Then the limb developed compensatory-adaptive processes, namely reconstruction of the venous system accompanied by formation of collateral main veins and lymphatic collectors that partially compensated for abnormal venous blood flow. Prolonged impairment of hemocirculation and venous congestion led to anoxia of venous walls, sclerosis, dystrophic, inflammatory and focal sclerotic lesions in the adjacent tissue. This experimental model can be successfully used for solving the problems of the pathogenesis and therapy of chronic venous failure.
The usefulness of immunostaining with anti-desmoplakin antibody for light microscopic identification of lymphatic vessels was examined in cryostat sections of the human tongue. The results were compared with laminin, 5'-nucleotidase (5'-Nase), and factor VIII staining. Immunoelectron microscopic observation was also performed to confirm that the vessels reacting with anti-desmoplakin were lymphatic vessels. Under the immunoelectron microscopic, the vessels reacting with anti-desmoplakin showed ultrastructural features characteristic of lymphatic vessels: thin endothelial walls, no or incomplete basal lamina, open junctions, and overlapping endothelium. In general, lymphatic vessels identified by anti-desmoplakin reacted strongly with 5'-Nase, but showed weak or no reactivity with anti-laminin and anti-factor VIII. Blood vessels showed no reactivity with anti-desmoplakin, but reacted strongly with anti-laminin and anti-factor VIII. However, some blood and lymphatic vessels showed intermediate reactivity with anti-laminin, anti-factor VIII, and 5'-Nase. It was difficult to identify these as blood or lymphatic vessels only by the reactivity differences. The results indicate that anti-desmoplakin antibody specifically distinguishes lymphatic vessels and is useful for studying the fine distribution of lymphatic vessels under light microscopy.
This paper reports on how lymphatic vessels and their smooth muscle cells develop in the diaphragm of postnatal rats. Lymphatic endothelial cells in the diaphragm were labeled by an intraperitoneal injection of DiI-labeled acetylated low-density lipoprotein (DiIac-LDL). During postnatal week 1, DiI-ac-LDL was detected in many free cells in addition to distinct endothelial cells that formed lymphatic vessels. Occasionally, saccular lymphatics isolated from previously formed lymphatics were recognized; these were referred to as lymphatic islands. The DiI-ac-LDL-labeled free and lymphatic endothelial cells showed immunoreactivity for CD 34 and Flt-4, but most of them did not express either OX 62 or ED 1 immunoreactivity, with only some showing ED 1 immunoreactivity. This suggests that most of the DiI-ac-LDL-labeled elements were lymphatic endothelial cells, and that some were macrophages. After postnatal week 1, the DiI-ac-LDL positive cells were restricted to lymphatic vessels. Until postnatal week 6, lymphatic vessels increased as the diaphragm enlarged. Towards the end of postnatal week 2, free cells expressing alpha-smooth muscle actin (alpha-SMA) immunoreactivity increased in the diaphragm, and some of these were in contact with lymphatics. A coarse plexus of smooth muscle cells surrounding the lymphatic vessels first appeared at postnatal week 2, and this plexus became denser with age. Our findings indicate that lymphatic vessels are formed not only by sprouting from previously formed lymphatic vessels but also by migrating endothelial cells, and that smooth muscle cells may be differentiated from mesenchymal cells to form a plexus surrounding the lymphatic vessels.