Vasculogenesis in Diabetes-Associated Diseases: Unraveling the Diabetic Paradox

Abstract

During several decades it was thought that in the adult, vascular growth and remodelling was exclusively dependent on the activation of angiogenesis, being the process of vasculogenesis restricted to embryonic life (Risau & Flamme, 1995; Risau, 1997). This long-lasting belief has come to an end in the late nineties, with the isolation from adult peripheral blood (PB) of angioblast-like circulating Endothelial Progenitor Cells (EPCs) (Asahara et al., 1997). The discovery of bone marrow (BM)-derived EPCs with angioblastic morphological and functional properties was a landmark in vascular biology that forever has changed the concept of neovascularization. Numerous studies have demonstrated that EPCs residing in the BM could be mobilized to the peripheral circulation, migrate to neoangiogenic sites and partake in vivo in the pathophysiological development of vascular networks, by differentiating into functional, mature endothelial cells (ECs) (Asahara et al., 1999a, 1999b; Goon et al., 2007; Grant et al., 2002; Lyden et al., 2001; Takahashi et al., 1999). However, much controversy has accompanied this field over time, particularly regarding the phenotypic characterization of EPCs. In fact, this cell population does not have specific cell surface markers, sharing a diversity of membrane receptors with other BM-derived cells (Hristov et al., 2003; Peichev et al., 2000). Additionally, several subsets of EPCs have been identified and together with other lineages of precursor cells were found to be differentially recruited to neovascular foci contributing synergistically to vasculogenic neoformation (Gulati et al., 2003; Hur et al., 2004; Lyden et al., 2001; Yoder et al., 2007; Yoon et al., 2005a). Since their identification, an increasing body of evidence has definitely revealed the important properties and roles played by EPCs in several vascularrelated diseases, such as peripheral vascular disease (Asahara et al., 1999a, 1999b; Takahashi et al., 1999), tumor neovascularisation (Asahara et al., 1999a, 1999b; Lyden et al., 2001) and vascular complications associated to diabetes (Goon et al., 2007; Grant et al., 2002; Egan et al., 2008; Fadini et al., 2005). The metabolic alterations present in diabetic individuals are known to profoundly affect vascular biology, being responsible for the impairment of macroand microvascular beds (Fadini et al., 2006a; Werner et al., 2005). Diabetes associated vascular complications involve distinct modifications in neovascular formation, which is reduced in ischemic heart and limbs and increased in the retina, defining the diabetic paradox (Ciulla et al., 2003). The vasculogenic process seems to play a central dual role in this paradoxal puzzle: systemically, diabetes-associated hyperglycemia, insulin resistance, hypertension and oxidative stress, can simultaneoulsy