MECHANISMS OF ANGIOGENESIS
Angiogenesis occurs by the budding of new blood vessels from existing vessels (Fig. 14.1). Inflammation and hypoxia are the two major stimuli for new vessel growth. Hypoxia regulates angiogenesis predominantly by activating transcription factors, hypoxia-inducible factors (HIF) 1 and 2, which, in turn, activate the angiogenesis gene expression cascades, including vascular endothelial growth factor (VEGF), platelet growth factor, angiopoietin 1 and 2, as well as stromal cell-derived factor 1α. Based on this concept, HIF-1 promotes sprouting of blood vessels and neovascularization by homing of stem cells and enhancing vascular endothelial cell proliferation. HIF-2 mediates vascular maintenance. Inflammation stimulates angiogenesis mainly by the secretion of inflammatory cytokines derived primarily from macrophages. In either of these events, the result is production of VEGF and other potent angiogenic peptides. VEGF interacts with specific receptors on endothelial cells that, in turn, activate pathways to break down the extracellular matrix and stimulate proliferation and migration toward an angiogenic stimulus and recruitment of stem cells, pericytes, and smooth muscle cells to establish the three-dimensional structure of a blood vessel. After making appropriate connections with the vascular system, the newly formed vessel is capable of maintaining blood flow and providing oxygen to the tissue in need.
FIG 14.1 Mechanisms of Angiogenesis. bFGF, Basic fibroblast growth factor; HIF-1, hypoxia inducible factor; TGF-β, transforming growth factor beta; VEGF, vascular endothelial growth factor.
Angiogenesis occurs in numerous circumstances, some of which are necessary for normal development and organ function. In other circumstances, angiogenesis is a maladaptive response to local injury or stress. During development, the formation of every organ system is dependent on angiogenic events; the cardiovascular system is the first organ system to function during embryogenesis. In women, the menstrual cycle is dependent on cyclic angiogenesis that is stimulated in part by reproductive hormones. However, most angiogenesis in adults occurs in pathological conditions or as a response to injury. Tumor growth and metastasis, diabetic vascular disease (including retinopathy), inflammatory arthritides, and wound healing are some of the processes that depend on angiogenesis. In addition, the invasion of ischemic tissues with new capillaries and the development of a collateral circulation to supply occluded vessels, which may occur in chronic obstructive coronary disease, are angiogenic processes.
Refractory coronary ischemia, particularly in patients with decreased LV function who may not be candidates for revascularization, remains a difficult clinical problem. Recognition of angiogenesis as an endogenous mechanism for perfusion of ischemic tissues raises the possibility that angiogenic factors or cells that produce them might be therapeutic tools for patients with refractory ischemia. Angiogenesis seems to be amenable to gene therapy approaches. Although gene therapy may induce angiogenesis and improve perfusion in a wide spectrum of animal models of ischemia, thus far the usefulness of these approaches in humans has been limited. New vessel growth is a process that occurs over weeks to months (precluding single-dose therapies). However, after new vessels form, they are not likely to regress if they are conduit vessels; therefore long-term therapy may not be necessary. Gene delivery by plasmids and adenoviruses can be directed to occur within this “angiogenic window,” raising hope for angiogenic gene therapies in chronic ischemic syndromes.
Gene therapy approaches to deliver VEGF to patients with ischemic coronary and peripheral vascular diseases have progressed, albeit not at the rates hoped for based on initial investigations in the 1990s. The use of angiogenic gene therapy still has tremendous potential for patients with refractory ischemic heart disease who otherwise have no options. Because angiogenesis is a new mechanism for treating this disease, it should be additive to the effects of pharmacological agents (β-blockers, aspirin, and nitrates). The possibility of the creation of new, long-lived conduit vessels offers the potential for a “cure” because these new vessels could provide relief long after the effects of VEGF or other angiogenic factors have dissipated.
However, it is not yet clear that angiogenesis, which predominantly involves the formation of new capillaries, creates vessels with the capacity to significantly increase blood flow to ischemic tissues. Uncontrolled capillary growth may cause hemangioma formation, which would not be beneficial and might be deleterious. Few data are available that allow prediction of the appropriate dose, location, and duration of angiogenic gene therapy. In therapy for myocardial ischemia, required invasive approaches are associated with appreciable morbidity. Despite predictions of side effects based on diseases with known angiogenic components, little is known about side effects of angiogenic therapies in humans. Of greatest concern is the possibility that angiogenic therapies will accelerate or unmask occult tumors or metastases, because it is well known that tumor growth is an angiogenesis-dependent process. Worsening diabetic neovascular complications, especially diabetic retinopathy, are also a concern, because of the prevalence of diabetes in patients with severe atherosclerotic disease.
Early clinical trials in angiogenesis have produced results that are variably interpreted, depending on the views of those reviewing these studies. Small, but statistically significant, improvements in pain-free exercise duration have been demonstrated in angiogenesis trials involving the coronary vasculature (with chest pain as the limiting symptom) and the peripheral vasculature (in patients with limiting claudication). These data support the concept of clinical angiogenesis. An opposing view is that because the improvements are modest, these studies have fallen short of demonstrating an important clinical benefit; moreover, thus far, no studies have shown an effect on mortality or major morbidity.
Whether angiogenesis is an effective approach, how and when to apply angiogenic agents, and the possible side effects of angiogenic stimulants are still under investigation. Long-term studies are necessary to definitively exclude adverse consequences (e.g., tumor promotion).