Lymphatic vasculature development

The lymphatic system is vital for maintaining the colloid osmotic volume (or pressure) and for absorbing lipids from the intestinal tract. The lymphatic system is also essential for the immune response to infectious agents, and during cancer progression; metastatic spreading of malignant cells occurs through the lymphatic and blood vessels.Lymphangiogenesis is the growth of the lymphatic vessels, and congenital or acquired dysfunction of the lymphatic system can result in the formation of lymphoedema — a disorder that results in thickening of the skin and accumulation of adipose tissue.The working model for lymphatic vasculature development proposes that blood venous endothelial cells are the ground condition from which a lymphatic endothelial cell phenotype will be progressively acquired by the stepwise expression of different gene products. In this model, expression of the transcription factor prospero-related homeobox 1 (Prox1) by venous endothelial cells is sufficient to initiate the programme that leads to lymphatic endothelial cell-type specification, and lack of Prox1 activity represses the whole programme of lymphatic differentiation.Nonsense mutations in vascular endothelial growth-factor receptor 3 (VEGFR3) have been identified in patients with hereditary lymphoedema and its ligand, VEGFC, was identified as a potent inducer of lymphatic sprouting. Overexpression of VEGFC through the use of a recombinant adenovirus promotes therapeutic lymphangiogenesis in a rabbit model of acquired lymphoedema as well as tumour lymphangiogenesis. Mutations in the forkhead transcription factor FOXC2 have been identified in patients with lymphoedema–distichiasis syndrome.Other available mouse models with lymphatic vasculature alterations include: podoplanin-deficient mice, which have lymphatic defects associated with diminished lymphatic transport, congenital lymphoedema and dilation of lymphatic vessels; neuropilin-2-deficient mice show an absence or severe reduction in the number of small lymphatic vessels and capillaries; and functional inactivation of angiopoietin 2 indicated that this molecule is required for postnatal blood vascular remodelling and proper development of the lymphatic vasculature.