Reversal of cellular roles in angiogenesis: implications for anti-angiogenic therapy

Whether occurring during embryonic development, in pathophysiological conditions, such as wound healing/tissue regeneration, or in fully pathological conditions, such as cancer and inflammatory diseases, angiogenesis is traditionally thought to be a strongly endotheliumdriven process. In fact, the main features of the angiogenic model, largely preserved as first proposed by Folkman [1] in 1971, implicate endothelial cells as primary effectors of the tubulogenesis process [2]. As depicted in figure 1a, pro-angiogenic growth factors (especially VEGF) trigger endothelial cell activation, proliferation and motility. In addition to resident endothelial cells, circulating endothelial precursors may also participate in the formation of interconnected neotubules [3]. Another crucial role is played by local pericytes or bone marrow-derived pericyte progenitors [4-6]. According to the angiogenesis dogma, pericytes are recruited by migrating endothelial cells to confer stability to nascent vascular structures [2,4-7]. Indeed, targeting pericytes through NG2 proteoglycan [8] or PDGFRβ [5,6] strongly impacts neovasculogenesis and may also affect lymphangiogenesis.