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 mac romolecules that have escaped from blood capillaries and entered the inters titium. In conjunction with interspersed lymph nodes and lymphoid organs, t he lymphatic vasculature also acts as a conduit for trafficking immune cell populations. Echoing the explosion of knowledge about blood vessel angioge nesis (properly termed "hemangiogenesis"), the past two decades have also w itnessed a series of significant, yet less-noticed discoveries bearing on " lymphangiogenesis," along with delineation of the spectrum of lymphedema-an giodysplasia syndromes. Failure of lymph transport promotes a brawny protei naceous edema of the affected limb, organ, or serous space that is disfigur ing, disabling, and on occasion even life-threatening. Key members of the v ascular endothelial growth factor (VEGF) and angiopoietin families of vascu lar growth factors (and their corresponding tyrosine kinase endothelial rec eptors) have been identified which preferentially influence lymphatic growt h and, when manipulated in genetically engineered murine models, produce ab errant "lymphatic phenotypes." Moreover, mutations in VEGF receptor and for khead family developmental genes have now been linked and implicated in the pathogenesis of two familial lymphedema-angiodysplasia syndromes. Thus, re cent advances in "molecular lymphology" are elucidating the poorly understo od development, physiology, and pathophysiology of the neglected lymphatic vasculature. In combination with fresh insights and refined tools in "clini cal lymphology," these advances should lead not only to earlier detection a nd more rational classification of lymphatic disease but also to better the rapeutic approaches, including designer drugs for lymphangiostimulation and lymphangioinhibition and gene therapy to modulate lymphatic growth. (C) 20 01 Wiley-Liss, Inc.