**5. The RAS and endothelial progenitor cells**

The identification of circulating endothelial progenitor cells (EPCs) has introduced the concept of postnatal vasculogenesis. EPCs could originate from haematopoietic stem cells (HSCs) or MSCs [22, 23]. Also, the EPCs existing in the adventitial layer of vessels have the ability to differentiate into adult endothelial cells [24]. Different factors such as ischaemia, vascular damage and even physical exercise result in the recruitment of circulating EPCs and thus neovascularization and restoration of endothelial functionality [25, 26]. In this context, the improvement of myocardial perfusion after EPC transplantation has been observed in clinical trials [27]. Several mechanisms have been suggested regarding EPCs mobilization. For instance, it was observed that ischaemic lesions release angiogenic factors like VEGF and activate MAPK or the RAS-signalling pathways [28], which increase EPCs migration.

Despite the important role of vascular endothelium in cardiovascular disease (CVD), their limited regeneration capacity remains a vital problem. EPCs improve angiogenesis and participate in endothelium recovery subsequent to vascular injuries [29]. Cardiovascular diseases (CVDs) are directly related to both the decline of EPC mobilization and the number of EPCs present in the damaged site. In this context, Ang II stimulates EPCs migration to ischaemic regions and commences vascularization through VEGF-associated endothelial nitric oxide synthase [30]. The activation of NAPH and subsequent ROS (reactive oxygen species) generation constitutes the stimulatory impact of Ang II on EPCs that is required for normal EPC function. However, the long-term activation of NADPH and oxidative stress is concomitant with cell senescence [31]. Moreover, acute high-dose exposure to Ang II has been shown to negatively modulate EPC function in the hind limb ischaemic rat model [32].
