Current topics of physiology and pharmacology in the lymphatic system

Ohhashi, Toshio; Mizuno, Risuke; Ikomi, Fumitaka; Kawai, Yoshiko

doi:10.1016/j.pharmthera.2004.10.009

Cited by 84 publications

(89 citation statements)

References 129 publications

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“…NO regulates the vasomotor activity of lymphatic microvessels, 8,28 inducing dilation, and it may act as a lymphangiogenetic factor through interaction with VEGF-C, as previously demonstrated in breast cancer and head and neck squamous cell carcinomas. 5,29 Interestingly, VEGF-C-overexpressing melanomas showed enhanced tumor angiogenesis, suggesting a coordinated 30,31 CD105 is an endothelial marker that reacts uniquely with endothelial cells of newly formed vessels, and, specifically of immature tumor blood vessels.…”

Section: Discussionmentioning

confidence: 54%

“…[2][3][4][5] Tumor-cell-derived NO has been proposed to be an important mediator of tumor angiogenesis and metastasis formation by directly inducing vessel dilation, promotion of blood flow and vascular permeability and endothelial cell proliferation through upregulation of vascular endothelial growth factor (VEGF) and basic fibroblastic growth factor. 6,7 In addition, more recent observations indicate that NO is involved in the regulation of lymphatic vessels permeability and flow 8 and we have recently demonstrated that iNOS activity correlated with lymphangiogenesis and spread to lymph nodes in head and neck squamous cell carcinoma. 5 It is possible that in the tumor microenvironment NO stimulates angiogenesis and/or lymphangiogenesis cooperatively with other proangiogenic and lymphangiogenic growth factors.…”

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confidence: 96%

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Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis

et al. 2009

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Cutaneous melanoma preferentially metastasizes via the lymphatic route. However, the mechanisms of lymphatic invasion and metastasis to regional lymph nodes are poorly understood. Nitric oxide is a free radical molecule synthesized from L-arginine by nitric oxide synthases that plays a critical role in various physiological and pathological processes, including tumor growth and angiogenesis. We have tested whether inducible nitric oxide synthase expression correlates with lymphatic vessel density identified with D2-40 antibody and/or blood microvessel density identified with CD105/endoglin in a series of melanocytic nevi (n ¼ 28) and cutaneous melanomas (n ¼ 38), representative of various pT. Inducible nitric oxide synthase expression was significantly lower in melanocytic nevi in comparison with primary and metastatic melanomas (Po0.001). Mean microvessel density was significantly higher in primary and metastatic melanomas in comparison with melanocytic nevi (Po0.001 for intratumoral and P ¼ 0.001 for peritumoral vessels). Vertical growth phase melanomas showed a higher intratumoral microvessel density in comparison with radial growth phase melanomas (P ¼ 0.02). The number of peritumoral lymphatics was significantly lower in nevi as compared with primary and metastatic melanomas (P ¼ 0.01). No correlation between microvessel or lymphatic vessel and clinical outcome was found in melanomas. A significant direct correlation was observed between inducible nitric oxide synthase immunostaining in melanocytic tumor cells and the density of lymphatic vessels (peritumoral: P ¼ 0.001; intratumoral: P ¼ 0.08), and the density of peritumoral blood microvessel (P ¼ 0.02). Our findings support the hypothesis that inducible nitric oxide synthase is implicated not only in blood, but also in lymphatic vascular neoformation in melanoma. Mechanistic studies are needed to address the possibility that inducible nitric oxide synthase controls lymphangiogenesis, dissemination and lymphatic borne metastases. Keywords: iNOS; CD105; D2-40; microvessel density; melanoma; nevi Cutaneous melanoma metastasizes at least initially through the lymphatic route and lymph node metastasis is currently still a major determinant for patients staging and clinical management. The mechanisms of lymphatic invasion and metastasis to regional lymph nodes are mostly unknown and whether human tumors promote de novo lymphangiogenesis is still unclear. Although the pathways that regulate tumorrelated angiogenesis have been partially investigated, poor information is available on the processes that result in lymphangiogenesis in melanoma.Nitric oxide (NO) is a diatomic free radical molecule synthesized from L-arginine by NO synthases (NOS) that plays a critical role in various physiological and pathological processes, including tumor growth. Although the Ca 2 þ -dependent isoforms NOS1 and NOS3 are constitutively expressed by neural and endothelial cells, the Ca 2 þ -independent form (NOS2 or iNOS) can be induced by many cell types upon stimulation by inflamma...

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Section: Discussionmentioning

confidence: 54%

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Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis

et al. 2009

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“…Collecting lymphatic vessels can produce flow autonomously using smooth muscle cell (SMC)-driven contractions, which drive flow through one-way intraluminal valves and lymph nodes before its return to the blood circulation (10). Although studies of lymphatic pumping in large animals have given insights into lymphatic contraction (11)(12)(13)(14)(15), molecular control of this process is not well understood. Given the ready availability of molecular reagents, genetic knockouts, and disease models in mice, an in vivo murine model of lymphatic contraction will advance the field by dissecting the underlying molecular mechanisms under normal and pathological conditions.…”

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confidence: 99%

Impaired lymphatic contraction associated with immunosuppression

Liao

Cheng

Conner

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

265

321

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To trigger an effective immune response, antigen and antigen-presenting cells travel to the lymph nodes via collecting lymphatic vessels. However, our understanding of the regulation of collecting lymphatic vessel function and lymph transport is limited. To dissect the molecular control of lymphatic function, we developed a unique mouse model that allows intravital imaging of autonomous lymphatic vessel contraction. Using this method, we demonstrated that endothelial nitric oxide synthase (eNOS) in lymphatic endothelial cells is required for robust lymphatic contractions under physiological conditions. By contrast, under inflammatory conditions, inducible NOS (iNOS)-expressing CD11b + Gr-1 + cells attenuate lymphatic contraction. This inhibition of lymphatic contraction was associated with a reduction in the response to antigen in a model of immune-induced multiple sclerosis. These results suggest the suppression of lymphatic function by the CD11b + Gr-1 + cells as a potential mechanism of self-protection from autoreactive responses during on-going inflammation. The central role for nitric oxide also suggests that other diseases such as cancer and infection may also mediate lymphatic contraction and thus immune response. Our unique method allows the study of lymphatic function and its molecular regulation during inflammation, lymphedema, and lymphatic metastasis.

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“…Several studies have shown the involvement of the lymphatic endothelium in the NO-mediated modulation of lymphatic contractile activity. 11,[14][15][16] In particular, specific immunostaining of endothelial nitric oxide synthase (eNOS) was demonstrated in endothelial cells of bovine lymphatics 17 and in rat lymphatic endothelial cells. 18 In functional experiments it was demonstrated that precontracted dog thoracic duct rings relaxed to acetylcholine (ACh) or sodium nitroprusside (SNP).…”

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confidence: 99%

“…Because of the importance of the NO molecule released by lymphatic endothelium for the regulation of lymphatic contractility and flow in adult 11,14,16,27,[32][33][34] and aged 4,24,29 lymphatic vessels, in the discussed study 30 we implemented in vivo the local NOS blockade induced by topical administration of 100 lM of L-NAME. We compared the contractile behavior of MLV and lymph flow in adult and aged groups before and after the L-NAME administration.…”

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confidence: 99%

Aged Lymphatic Contractility: Recent Answers and New Questions

Gashev

Chatterjee

2013

Lymphatic Research and Biology

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An overview is presented of recent findings related to biology of aging of the lymph transport system. The authors discuss recently obtained data on the aging-associated alterations of lymphatic contractility in thoracic duct and mesenteric lymphatic vessels; on comparisons of function of aged mesenteric lymphatic vessels in situ versus isolated specimens and important conclusions which arose from these studies; on aging-associated changes in functional status of mast cells located close to aged mesenteric lymphatic vessels; on evidence of presence of oxidative stress in aged lymphatic vessels and changes in arrangement of muscle cells in their walls. The authors conclude that future continuation of the research efforts in this area is necessary and will be able to provide not only novel fundamental knowledge on the biology of lymphatic aging, but also will create solid foundation for the subsequent developments of lymphatic-oriented therapeutic interventions in many diseases of the elderly.T he major task of the lymphatic system is lymph transport. This system of initial capillaries, transporting vessels, and nodes is designed to transport fluid, soluble molecules, and immune cells from the interstitium through the lymph nodes to the central veins. This system also provides the transportation route for inflammatory mediators, the products of tissue injury/destruction, foreign substances, and tumor cells. Dysfunctional lymph transport can result in a wide range of disturbances, including edema, altered immune cell trafficking, depressed immune function, and impaired lipid metabolism. The lack of knowledge on how aging affects lymphatic vessels certainly contributes to the situation when researchers and clinicians ignore lymph transport-related components of various diseases. Thus, investigation of the mechanisms affecting lymphatic contractile function during aging are extremely important for ongoing attempts to better understand the lymphatic system and to discover the pathogenesis and effective treatment of various aging-associated disorders.Until recently, there were no published reports on systematic studies on aging-associated changes in the active lymph pumps. Due to the profound difficulty of measuring lymph flow in vivo, there are only a few reports demonstrating the measurements of reduced lymph flow in aged animals. [1][2][3] In particular, it was reported 3 that aging significantly decreases lymph flow from the main mesenteric lymph duct by *60% between ages of 3 and 22 mo in rats.During the last years, we obtained important functional and molecular evidence of the aging-associated alterations of contractility in lymphatic vessels, which already widened our knowledge on the biology of aged lymph flow. On the other hand, our recent studies raise new important questions that may link several diseases to impaired coordination between lymphatic function and function of other systems in the aged body. While this review provides some recent answers on current questions in biology of lymphatic aging,...

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Current topics of physiology and pharmacology in the lymphatic system

Cited by 84 publications

References 129 publications

Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis

Inducible nitric oxide synthase expression in melanoma: implications in lymphangiogenesis

Impaired lymphatic contraction associated with immunosuppression

Aged Lymphatic Contractility: Recent Answers and New Questions

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