VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes (original) (raw)
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An important role of lymphatic vessel activation in limiting acute inflammation
Blood, 2011
In contrast to the established role of blood vessel remodeling in inflammation, the biologic function of the lymphatic vasculature in acute inflammation has remained less explored. We studied 2 established models of acute cutaneous inflammation, namely, oxazolone-induced delayed-type hypersensitivity reactions and ultraviolet B irradiation, in keratin 14-vascular endothelial growth factor (VEGF)-C and keratin 14-VEGF-D transgenic mice. These mice have an expanded network of cutaneous lymphatic vessels. Transgenic delivery of the lymphangiogenic factors VEGF-C and the VEGFR-3 specific ligand mouse VEGF-D significantly limited acute skin inflammation in both experimental models, with a strong reduction of dermal edema. Expression of VEGFR-3 by lymphatic endothelium was strongly down-regulated at the mRNA and protein level in acutely inflamed skin, and no VEGFR-3 expression was detectable on inflamed blood vessels and dermal macrophages. There was no major change of the inflammatory ce...
Lymphatics at the crossroads of angiogenesis and lymphangiogenesis
Journal of Anatomy, 2004
The lymphatic system is implicated in interstitial fluid balance regulation, immune cell trafficking, oedema and cancer metastasis. However, the sequence of events that initiate and coordinate lymphatic vessel development (lymphangiogenesis) remains obscure. In effect, the understanding of physiological regulation of lymphatic vasculature has been overshadowed by the greater emphasis focused on angiogenesis, and delayed by a lack of specific markers, thereby limiting this field to no more than a descriptive characterization. Recently, new insights into lymphangiogenesis research have been due to the discovery of lymphatic-specific markers and growth factors of vascular endothelial growth factor (VEGF) family, such as VEGF-C and VEGF-D. Studies using transgenic mice overexpressing VEGF-C and VEGF-D have demonstrated a crucial role for these factors in tumour lymphangiogenesis.
The Journal of Immunology, 2010
Vascular endothelial growth factor A (VEGF-A) is a prominent growth factor for both angiogenesis and lymphangiogenesis. Recent studies have shown the importance of VEGF-A in enhancing the growth of lymphatic endothelial cells in lymph nodes (LNs) and the migration of dendritic cells into LNs. VEGF-A is produced in inflamed tissues and/or in draining LNs, where B cells are a possible source of this growth factor. To study the effect of B cell-derived VEGF-A, we created transgenic mice (CD19 Cre /hVEGF-A fl) that express human VEGF-A specifically in B cells. We found that the human VEGF-A produced by B cells not only induced lymphangiogenesis in LNs, but also induced the expansion of LNs and the development of high endothelial venules. Contrary to our expectation, we observed a significant decrease in the Ag-specific Ab production postimmunization with OVA and in the proinflammatory cytokine production postinoculation with LPS in these mice. Our findings suggest immunomodulatory effects of VEGF-A: B cell-derived VEGF-A promotes both lymphangiogenesis and angiogenesis within LNs, but then suppresses certain aspects of the ensuing immune responses.
Breaking a Vicious Circle: Lymphangiogenesis as a New Therapeutic Target in Wound Healing
Biomedicines
The lymphatic system is of fundamental importance in maintaining a fluid balance in the body and tissue homeostasis; it drains protein-rich lymph from the interstitial space and facilitates the release of cells that mediate the immune response. When one tissue is damaged, more cells and tissues work to repair the damaged site. Blood and lymph vessels are particularly important for tissue regeneration and healing. Angiogenesis is the process of the formation of new blood vessels and is induced by angiogenic factors such as VEGF-A; VEGF-C/D-induced lymphangiogenesis and both occur simultaneously during wound healing. After the inflammatory phase, lymphatic vessels suppress inflammation by aiding in the drainage of inflammatory mediators; thus, disorders of the lymphatic system often result in chronic and disabling conditions. It has recently been clarified that delayed wound healing, as in diabetes, can occur as a consequence of impaired lymphangiogenesis. In this review, we have high...
International …, 2004
Recruitment of dendritic cells (DCs) to lymph nodes (LNs) is pivotal to the establishment of immune response. Whereas DCs have been proven to undergo afferent lymphatic pathway to enter LNs from peripheral tissues, a question remains if DCs also migrate into LNs directly from the circulation. Here we demonstrate that plasmacytoid DC (pDC) precursors can transmigrate across high endothelial venules (HEVs) of in¯amed LNs in mice. Bacterial infection induces a signi®cant number of pDC and myeloid DC (mDC) precursors into the circulation. Both subsets express a common set of chemokine receptors except CXCR3, display parallel mobilization into the blood, but show distinct traf®cking pathway to the LNs. In a short-term homing assay, whereas mDC precursors migrate to peripheral tissues and subsequently to draining LNs, pDC precursors directly enter the LNs in a CXCL9 and E-selectin dependent manner. Tumor necrosis factor-a controls not only DC precursor mobilization into the blood but also chemokine up-regulation on LN HEVs. A similar traf®cking pathway is observed also in viral infection, and CXCR3 ±/± micederived pDC precursors show defective trans-HEV migration. This study clari®es the in¯ammationdependent, chemokine-driven distinct property of DC precursor traf®cking.
Proceedings of the National Academy of Sciences, 2012
Lymphatic vessel growth or lymphangiogenesis occurs during embryonic development and wound healing and plays an important role in tumor metastasis and inflammatory diseases. However, the possibility of noninvasive detection and quantification of lymphangiogenesis has been lacking. Here, we present the Vegfr3 EGFPLuc mouse model, where an EGFP-luciferase fusion protein, expressed under the endogenous transcriptional control of the Vegfr3 gene, allows the monitoring of physiological and pathological lymphangiogenesis in vivo. We show tracking of lymphatic vessel development during embryogenesis as well as lymphangiogenesis induced by specific growth factors, during wound healing and in contact hypersensitivity (CHS) -induced inflammation where we also monitor down-regulation of lymphangiogenesis by the glucocorticoid dexamethasone. Importantly, the Vegfr3-reporter allowed us to tracking tumor-induced lymphangiogenesis at the tumor periphery and in lymph nodes in association with the metastatic process. This is the first reporter mouse model for luminescence imaging of lymphangiogenesis. It should provide an important tool for studying the involvement of lymphangiogenesis in pathological processes. bioluminescence | fluorescence | knockin mouse