New Insights into the Molecular Control of the Lymphatic Vascular System and its Role in Disease

Abstract

The cutaneous lymphatic system plays an important role in the maintenance of tissue fluid homeostasis, in the afferent phase of the immune response, and in the metastatic spread of skin cancers. However, the lymphatic system has not received as much scientific attention as the blood vascular system, largely due to a lack of lymphatic-specific markers and to the dearth of knowledge about the molecular regulation of its development and function. The recent identification of genes that specifically control lymphatic development and the growth of lymphatic vessels (lymphangiogenesis), together with the discovery of new lymphatic endothelium-specific markers, have now provided new insights into the molecular mechanisms that control lymphatic growth and function. Moreover, studies of several genetic mouse models have set the framework for a new molecular model for embryonic lymphatic vascular development, and have identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. These scientific advances have also provided surprising evidence that malignant tumors can directly promote lymphangiogenesis and lymphatic metastasis, and that lymphatic vessels play a major role in cutaneous inflammation and in the cutaneous response to UVB irradiation.

Simple vertebrate models for chemical genetics and drug discovery screens: Lessons from zebrafish and Xenopus

“…Angiogenesis and lymphangiogenesis are essential for embryonic development and organogenesis, but also play important roles in tissue regeneration, chronic inflammation, and tumor progression (Carmeliet, 2003;Alitalo et al, 2005;Cueni and Detmar, 2006). Despite the significant advances in developing antiangiogenic therapies of recent years, the identification of novel drugs targeting the blood and lymph vasculature is of high priority.…”

Pathways Targeting Tumor Lymphangiogenesis

“…Recent studies indicate a major role of the VEGF-A/VEGFR-2 signaling pathway in lymphangiogenesis (18). VEGF-A induces proliferation of lymphatic endothelial cells in vitro (19), and injection of adenoviral murine VEGF-A resulted in pronounced in vivo lymphangiogenesis in mouse ear skin (20).…”

Reduction of lymphatic vessels in photodamaged human skin

“…Because the endothelial cells of cutaneous lymphatic capillaries are attached to interstitial collagen and elastic fibers via fibrillincontaining anchoring filaments, degradation of elastic fibers in chronically UVB-damaged skin likely leads to reduced attachment of lymphatic endothelium to the extracellular matrix and thus might lead to rarefication of lymphatic vessels. It will be of great interest to investigate whether promotion of lymphatic growth and/or function by specific lymphangiogenesis factors such as VEGF-C or VEGF-D -that activate the lymphaticspecific receptor VEGFR-3 -or other recently identified growth factors [6], might attenuate UVB-induced cutaneous photodamage by increasing the number and/or the draining function of cutaneous lymphatic vessels. Rarefication of lymphatic vessels in photodamaged facial skin.…”

“…Together, these findings indicate that the cutaneous blood vasculature plays a critical role in the mediation of photodamage. In contrast, the role of cutaneous lymphatic vessels in the response to UVB irradiation has remained unknown.Lymphatic vessels play a crucial role in the maintenance of tissue fluid homeostasis [6], and our recent results obtained in mouse models indicate that impairment of lymphatic vessel function is involved in the mediation of acute UVB-induced skin damage in mice because of increased leakiness of lymphatic vessels that was induced by enhanced levels of VEGF-A [7;8]. To investigate the consequences of chronic UVB irradiation of human skin on cutaneous lymphatic vessels, we obtained skin samples from the face (sun-exposed skin; 2-mm punch biopsies from the crow's feet area not including wrinkles) and from the buttocks (non-sunexposed skin; 4-mm punch biopsies) of 17 healthy Korean volunteers.…”