THE EMILIN1-α4/α9 INTEGRIN INTERACTION IS CRUCIAL IN LYMPHATIC VESSEL FORMATION AND MAINTENANCE

Lymphatic system is the second circulatory system and it is crucial for the maintenance of tissue interstitial fluid balance and it plays important roles in human diseases, including lymphedema, chronic inflammation and cancer metastasis. Lymphatic vasculature is divided essentially in two types of vessels: capillaries and collectors. Lymphatic capillaries allow absorption of fluid from interstitium whereas lymphatic collectors transport the lymph to lymph nodes and in the end in the blood circulation. A previous work demonstrated that EMILIN1, an extracellular matrix glycoprotein associated with elastic fibers, has a crucial role in the proper formation of lymphatic capillaries. Emilin1-/- mouse is the first abnormal lymphatic phenotype associated with an extracellular matrix component deficiency: enlargement of lymphatic vessels in several tissues and reduction of anchoring filaments. This morphological alterations cause impair of lymph uptake, increase of leakage and the development of a mild lymphedema condition. Moreover, through the engagement with by α4β1 integrin, EMILIN1 exerts a regulatory role in cell proliferation: in Emilin1-/- background there is an increase of proliferative rate. In this study we focus our interest on the role of EMILIN1 in the lymphatic vessel formation process. Our results show that EMILIN1, expressed in embryonic, postnatal and adult mouse valve structures, regulates lymphatic valve formation, maturation and maintenance. Emilin1-/- mice exhibit an immature vessel and valve leaflet structures, which affect also their functionality. We demonstrate that also in the lymphatic contest EMILIN1 is able to regulate cell proliferation. Moreover this extracellular matrix protein influences also the migratory ability of the endothelial lymphatic cells. The regulatory ability of EMILIN1 in the lymphatic is mediated by α9β1 integrin engagement. EMILIN1 influences the lymphangiogenesis process not only in the physiological but also in the pathological environment: it exerts a protective role in tumor growth, in tumor lymphangiogenesis as well as in metastatic spread to lymph nodes. Our data demonstrate for the first time a fundamental role for EMILIN1-α9β1 integrin interaction in lymphatic vasculature, especially in lymphatic valve formation and maintenance. Moreover our data underline the importance of this extracellular matrix component in displaying a regulatory function in proliferation and acting as a “guiding” molecule in migration of lymphatic endothelial cells.