Prof. Johannes Waltenberger,
The use of growth factors to stimulate vascular growth for the treatment of regional ischemia has developed into an area of remarkable scientific activities and attention. However, several large trials (FIRST, VIVA, RAVE, EuroInject 1) have failed to demonstrate efficiency. Based on recent insight into the mechanisms of vascular growth, namely novel signalling mechanisms, novel stimuli and deeper insight into vascular maturation, these limitations are likely to be overcome.
The term therapeutic angiogenesis is a concept that had first been introduced by the German gynecologist Michael Höckel in 1989 . The idea was to induce capillary growth in order to improve regional tissue perfusion and to improve tissue viability following surgery. Much has happened in the field since then. Major angiogenesis factors and their receptors have been identified, isolated, cloned and characterized. Preclinical data has accumulated which clearly proves the concept that angiogenic growth factors are capable of inducing vascular and collateral growth. This had been shown for VEGF-A, for bFGF as well as for other growth factors . Proof of concept had been achieved in animal models of both peripheral ischemia and regional myocardial ischemia in the early 1990’s.
The concept of collateral artery growth has been modified by the introduction of the term “arteriogenesis”, which describes the growth of mature arteries  of large caliber. The prevailing concept is that these mature collaterals arise for the most part from pre-existent small collaterals. Arteriogenesis can be induced by some of the classical angiogenic growth factors such as bFGF and VEGF-A, but also by other inflammatory mediators such as MCP-1 . Besides endothelial cells, arteriogenesis involves circulating monocytes, which are homing within the growing collateral artery and which are releasing a number of growth factors and cytokines including VEGF-A, bFGF, PDGF, IL-1, IL-6 and MCP-1. Therefore, therapeutic vascular growth consists of therapeutic angiogenesis and therapeutic arteriogenesis.
In 1996, first clinical evidence was presented for the feasibility of therapeutic angiogenesis, i.e. the therapeutic stimulation of the growth of the new vessels in peripheral artery occlusive disease (PAOD) . These initial studies were based on the availability of angiogenic growth factors such as vascular endothelial growth factor (VEGF) protein or cDNA, and on emerging tools in gene therapy. Since then, more than twenty clinical trials have been finished using either a growth factor protein or growth factor genes to enhance perfusion in ischemic hearts or ischemic limbs. These studies have provided evidence for the feasibility of the concept, as well as the safety of this modality. In contrast, there is only limited evidence for efficacy in controlled, randomized and double-blinded clinical trials, which is true for both coronary artery disease (CAD) and PAOD. In addition, the outcome of protein studies and gene therapy studies is comparable. The biggest of these studies were the FIRST  and the VIVA  trial (use of rFGF-2 intracoronary or rhVEGF-A165 intracoronary plus intravenous, respectively) for stimulating coronary collateral growth, the TRAFFIC  and the recent RAVE trial for PAOD. While the effects of bFGF in TRAFFIC were encouraging, the clinical benefit of VEGF in VIVA and RAVE was rather disappointing.
Table 1: Clinical studies on Therapeutic vascular growth in CAD (phase II and III)
Table 2: Clinical studies on Therapeutic vascular growth in PAOD (phase II and III)
It is therefore a challenge for vascular biology to define the possible shortcomings and to implement more efficient strategies to better transfer the preclinical concepts into the clinical situation.
Basic science has recently gained substantial insight into the mechanisms of vascular growth. I) Most importantly, the time period of the angiogenic or arteriogenic action was probably too short in most of the clinical studies as a prolonged action of growth factors is required for the maturation of persistent vessels . II) Moreover, basic research has uncovered novel mechanisms of how endothelial cells can be activated. Placental Growth Factor PlGF, a ligand for VEGF-receptor-1, is capable of activating VEGF-receptor-2 in an indirect fashion . Therefore, PlGF – either alone or in combination with other angiogenic factors – is a novel therapeutic candidate to be used in clinical trials It remains to be shown, whether some of the advantages seen in preclinical studies (no haemangioma formation, no edema) will finally hold true in the clinical situation. The translation of these basic findings into the clinical situation (i.e. development of new formulations and novel devices for delivery) is currently ongoing and holds promise for the final realization of the concept of therapeutic induction of vascular growth in chronic and critical ischemia.
Finally, the clinical circumstances may turn out to be crucial for the success of therapeutic induction of collateral growth. Diabetic individuals do not develop the same efficient collateral network as non-diabetics do . This may contribute to the fact that diabetic individuals have a higher mortality rate from cardiovascular causes than non-diabetics including a higher coronary event rate. It is well established that a reduced number of collaterals is associated with higher morbidity and mortality in patients with coronary artery disease . Ex vivo data have been generated in order to explain this clinically important observation. It has recently been shown, that monocyte recruitment should be impaired in diabetic individuals as ligand-induced migration of monocytes is impaired in diabetics . This implies that diabetes mellitus is an important predictor for reduced monocyte activation, which may be associated with a poorer therapeutic outcome in studies of therapeutic vascular growth.
Taken together, there is a significantly broadened basis for the concept of therapeutic vascular growth. Novel findings in vascular biology will be implemented in future clinical trials to therapeutically improve regional perfusion in CAD and PAOD.
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.
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Prof. J. Waltenberger Chairman of the Working Group on Pathogenesis of Atherosclerosis.
Department of Cardiology, University Hospital Maastricht, P. Debyelaan 25, P.O. Box 5800, 6202 AZ Maastricht, The Netherlands Tel: +31-43-387 5106 Fax: +31-43-387 5104 firstname.lastname@example.org
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