Therapeutic Angiogenesis - quo Vadis? This was the question left after several clinical trials probing the clinical applicability of a tried and proven experimental concept yielded mixed results. Patients reported relief from symptoms, at times in the placebo group as well. Nevertheless this achievement may be viewed as major success in a painful no-option situation. More objective endpoints were rarely met with pro-angiogenic growth factor protein application. As Jens Kastrup illustrates, this data set blunted some of the hopes associated with the concept of new vessel formation, a situation not profoundly changed with the advent of adenoviral based gene therapy. In great detail, Petra Korpisalo, Tuomas Rissanen and Seppo Yla-Herttuala scrutinize the strengths and weaknesses of this widely used vector system.
One of the potential factors causing the bench-to-bedside gap within the therapeutic angiogenesis concept is the difference between an otherwise healthy lab animal (even though a large one) and a patient population with various comorbidities confounding the principles of angiogenesis. Vadim Tchaikovski and Johannes Waltenberger illustrate the multiple dysfunctional elements in angiogenic signalling of diabetic patients. In real world coronary artery disease patients treated by percutaneous coronary interventions, Rohit Khurana and Michael Simons point to the problem of endothelial activation which is helpful for luminal endothelial regeneration, however, at the expense of advential neovascularization and increased neointima formation.
As the status quo in the therapeutic neovascularization field suggests, there is room for improvement. Mark Post, Richard Cornelussen and Frits Prinzen recapitulate the current molecular concepts of cardioprotection and explore the value of pre- and postconditioning for the (post)ischemic heart. One obstacle to patient treatment is targeting of therapeutic agents towards the region of ischemia. In the setting of severe arterial disease, using the venous system might be advan-tegous, as Peter Boekstegers and Christian Kupatt suggest. Even if expressed in the ischemic region, one factor might be less effective than a family of growth factors, i.e. driven by the same transcription factor. Karen Vincent and Ralph Kelly followed the integrative approach overexpressing a constitutively active HIF 1a/VP16 construct. In order to make therapeutic neovascularization last, Andrea Banfi, Philipp Fueglistaler and Roberto Gianni-Barrera focus on the unresolved issue of vessel maturation and provides stunning evidence for a successful partnership of VEGFs and PDGFs. Beyond the vascular tool box, Serena Zacchigna, Carmen Ruiz de Almodovar, Peggy Lafuste and Peter Carmeliet draw parallels between vascular and neuronal networks and provide novel therapeutic options. As a surprise candidates for induction of neovascularization, the cathelicidins as antimicrobiologic peptids were identified recently. Robert Bals and Rembert Koczulla summarize their experience with LL37, a human peptide of this family.
A separate collection of evolutionary concepts of neovascularization is dedicated to cell based approaches, which are at times more integral, at times more selective and regulated than mono- or bimolecular interventions, since instead of a factor a whole factory in principle capable of adapting to the environments demands is offered as therapeutic principle. An array of different adult and embryonic cell-based approaches is investigated to date, as Mathias Lamparter and Antonis Hatzopoulos point out, usually offering paracrine software rather than vasculo-specific hardware (building blocks). Olivier Feron traces the role of eNOS and its microenvironmental partner, caveolin-1, in the context of adult vasculogenesis, from mobiliazation of EPCs from bone marrow niches towards their recruitment to the ischemic musculature. Wulf Ito scrutinizes the role of monocytes/macrophages and resident vascular precursor cells for the induction of a neovasculatory response.
Reviewing the whole body of work, we can't deny the impression that the concept of therapeutic neovascularization is far from exhaustion. Instead, a variety of substantial improvements, at times break-throughs, at the conceptional level as well as at the delivery and vector level are currently being evolved. Therefore, this volume is presenting some of the most impressive steps towards a vital future of biological induction of new vessels. We are confident that this fascinating collection of experienced perspectives will offer fresh insights allowing to refine our understanding and therapeutic approaches of therapeutic neovascularization. Indeed, it is our conviction that scientific modifications of a fundamentally sound concept will enable its applicability in the not so distant future
Munich, December 2006
Elisabeth Deindl Christian Kupatt
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