Angiogenesis is essential for tumor growth beyond minimal size and is important in many other pathophysiological situations. It is widely anticipated that modulation of angiogenesis (inhibition in tumors, stimulation in vascular insufficiency) will provide important therapeutic benefit. Many different cytokines and growth factors express angiogenic activity, of these VPF/VEGF stands out because of its potency, selectivity for vascular endothelium, and its consistent overexpression in malignant tumors and in other clinical conditions in which angiogenesis plays an important role. Very recently, we have described for the first time that the neurotransmitter dopamine (DA), which has long been used in the treatment of Parkinson's disease (as well as the treatment of cardiac failure), and DA D2 receptor agonists, potently and selectively blocks VPF/VEGF-induced angiogenesis in vivo, whether induced by tumors or by an adenoviral construct engineered to express VPF/VEGF. The experiments proposed here are designed to investigate the mechanistic details by which DA or its related compounds inhibit VPF/VEGF-induced angiogenesis.
In Aim 1, we will examine how DA D2 receptor, a G-protein coupled receptor (GPCR), can influence VEGFR-2 signaling pathways. By utilizing genetic and pharmacological approaches, Aim 2 will focus to reveal how peripheral DA might affect normal and pathological angiogenesis mediated by VPF/NEGF.
In Aim 3, investigation will be carried out to define the role of DA and its related molecules as anti-angiogenic agents in both tumor ascites as well as solid tumor models. Moreover, we will examine whether DA or related compounds can be employed with other conventional drugs (such as Taxol) in preclinical settings. Furthermore, the role of DA in angiogenesis mediated by other angiogenic molecules will also be investigated in animal models. Developmental angiogenesis in the retinas of newborn rats will be utilized to test the effect of DA in normal physiological angiogenesis. Taken together, the proposed studies will draw an important conceptual link between angiogenesis and the nervous system and suggest that DA, already in clinical use for other purposes, may have value in anti-angiogenesis therapy.
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