Exp Physiol 90.3 pp 315–326 315 Experimental Physiology – Themed Issue Cardiovascular Genomics Paper Therapeutic angiogenesis and vasculogenesis for tissue regeneration Paolo Madeddu Experimental Medicine and Gene Therapy, National Institute of Biostructures and Biosystems, Osilo and Porto Conte Technological Park, Osilo (Sassari), Italy Department of Internal Medicine, Sassari University, Italy Chair of Experimental Cardiovascular Medicine, Bristol Heart Institute, University of Bristol, UK Therapeutic angiogenesis/vasculogenesis holds promise for the cure of ischaemic disease. The approach postulates the manipulation of spontaneous healing response by supplementation of growth factors or transplantation of vascular progenitor cells. These supplements are intended to foster the formation of arterial collaterals and promote the regeneration of damaged tissues. Angiogenic factors are generally delivered in the form of recombinant proteins or by gene transfer using viral vectors. In addition, new non-viral methods are gaining importance for their safer profile. The association of growth factors with different biological activity might offer distinct advantages in terms of efficacy, yet combined approaches require further optimization. Alternatively, substances with pleiotropic activity might be considered, by virtue of their ability to target multiple mechanisms. For instance, some angiogenic factors not only stimulate the growth of arterioles and capillaries, but also inhibit vascular destabilization triggered by metabolic and oxidative stress. Transplantation of endothelial progenitor cells was recently proposed for the treatment of peripheral and myocardial ischaemia. Progenitor cells can be transplanted either without any preliminary conditioning or after ex vivo genetic manipulation. Delivery of genetically modified progenitor cells eliminates the drawback of immune response against viral vectors and makes feasible repeating the therapeutic procedure in case of injury recurrence. It is envisioned that these new approaches of regenerative medicine will open unprecedented opportunities for the care of life-threatening diseases. (Received 18 January 2005; accepted after revision 2 March 2005; first published online 18 March 2005) Corresponding author P. Maddedu: National Institute of Biostructures and Biosystems, viale Sant’Antonio, 07033 Osilo (Sassari), Italy. Email: madeddu@yahoo.com Gene therapy is based on the transfer of DNA sequences to somatic cells for therapeutic purposes. The gene can be directly delivered to the host (in vivo gene transfer). Another strategy postulates the infection of cells in culture in order to make them capable of synthesizing and releasing the transgene product upon transplantation into a recipient organism (ex vivo gene transfer). One of the most promising applications of gene therapy is therapeutic angiogenesis, which postulates the local delivery of vascular growth factors to ischaemic tissues as a way to foster spontaneous collateralization. Preclinical trials with angiogenic growth factors showed great therapeutic potential under conditions of advanced age, diabetes, atherosclerosis or hypertension, where impairment of endogenous neovascularization response is responsible for significantly delayed healing. These studies have generated a wealth of information about the mechanisms and mediators of angiogenesis and arteriogenesis, which has led to the first randomized, controlled, phase II/III trials with recombinant growth factors or their genes (Yla-Herttuala et al. 2004). Recently, the use of progenitor cells has been proposed as a novel method to stimulate vascular regeneration. Endothelial progenitor cells (EPCs) can be harvested from bone marrow (BM). In addition, EPCs are present in circulating blood, in quantities sufficient to permit autologous transplantation. By virtue of their unique plasticity, progenitor cells can differentiate into vascular and non-vascular elements, thereby replacing various components damaged by ischaemic insult. Angiogenesis C  The Physiological Society 2005 DOI: 10.1113/expphysiol.2004.028571