Lymphangiogenesis and lymphangiodysplasia: from molecular to clinical lymphology

The lymph vascular system parallels the blood vasculature and as one of its key functions returns liquid and solutes to the bloodstream, including macromolecules that have escaped from blood capillaries and entered the interstitium. In conjunction with interspersed lymph nodes and lymphoid organs, the lymphatic vasculature also acts as a conduit for trafficking immune cell populations. Echoing the explosion of knowledge about blood vessel angiogenesis (properly termed "hemangiogenesis"), the past two decades have also witnessed a series of significant, yet less-noticed discoveries bearing on "lymphangiogenesis," along with delineation of the spectrum of lymphedema-angiodysplasia syndromes. Failure of lymph transport promotes a brawny proteinaceous edema of the affected limb, organ, or serous space that is disfiguring, disabling, and on occasion even life-threatening. Key members of the vascular endothelial growth factor (VEGF) and angiopoietin families of vascular growth factors (and their corresponding tyrosine kinase endothelial receptors) have been identified which preferentially influence lymphatic growth and, when manipulated in genetically engineered murine models, produce aberrant "lymphatic phenotypes." Moreover, mutations in VEGF receptor and forkhead family developmental genes have now been linked and implicated in the pathogenesis of two familial lymphedema-angiodysplasia syndromes. Thus, recent advances in "molecular lymphology" are elucidating the poorly understood development, physiology, and pathophysiology of the neglected lymphatic vasculature. In combination with fresh insights and refined tools in "clinical lymphology," these advances should lead not only to earlier detection and more rational classification of lymphatic disease but also to better therapeutic approaches, including designer drugs for lymphangiostimulation and lymphangioinhibition and gene therapy to modulate lymphatic growth.