Tissular insemination of progenitor endothelial cells: the problem, and a suggested solution.

The contribution of circulating precursor endothelial cells (CPEC) to adult angiogenesis is now well established. However, the mechanism of their tissular engrafting remains poorly understood. The classical paradigm of "sprouting" cannot accommodate the main features of the CPEC-based angiogenic process. Additionally, vasculogenesis based on the differentiation of angioblasts, as defined in the embryonic stages, is not applicable to adult neo-vascularization either. In search for a solution to this dilemma, I suggest that the ability of monocytes/macrophages to produce tunnels, as effect of their protease-dependent migration in the extracellular matrices, is instrumental for the tissular insemination of CPEC. Here I present in vivo and in vitro experimental evidence for the existence of tunnels, and for their colonization by monocytes/macrophages and by other cells, including CPEC. As a paradigm of CPEC behavior, the tunneling model (in an extended sense) may also explain the propagation of the endothelium with arteriolar phenotype within the pre-existent downstream capillary network. Thus, the sprouting mechanism might be a valid explanation for the formation of new capillaries and venules, whereas CPEC would contribute mostly, if not exclusively, to the extension of arteriolar branches of microvasculature. Adult angiogenesis occurs therefore as a multifunctional process based on intercellular cooperation, in which there are involved endothelial cells (EC) or their precursors, as well as other cell types. In specific circumstances, the lumen (i.e. the tunnel) may occur before the "definitive" microvessel. Therefore the very notion of microvessel may need to be extended, to include the tunnels.