Angiogenesis has an essential role in many important pathological and physiological settings. It has been shown that vascular permeability factor/vascular endothelial growth factor (VPF/VEGF), a potent cytokine expressed by most malignant tumors, has critical roles in vasculogenesis and both physiological and pathological angiogenesis. We report here that at non-toxic levels, the neurotransmitter dopamine strongly and selectively inhibited the vascular permeabilizing and angiogenic activities of VPF/VEGF. Dopamine acted through D2 dopamine receptors to induce endocytosis of VEGF receptor 2, which is critical for promoting angiogenesis, thereby preventing VPF/VEGF binding, receptor phosphorylation and subsequent signaling steps. The action of dopamine was specific for VPF/VEGF and did not affect other mediators of microvascular permeability or endothelial-cell proliferation or migration. These results reveal a new link between the nervous system and angiogenesis and indicate that dopamine and other D2 receptors, already in clinical use for other purposes, might have value in anti-angiogenesis therapy.

Here, we report an intrinsic property of gold nanoparticles (nanogold): they can interact selectively with heparin-binding glycoproteins and inhibit their activity. Gold nanoparticles specifically bound vascular permeability factor/vascular endothelial growth factor (VPF/VEGF)-165 and basic fibroblast growth factor, two endothelial cell mitogens and mediators of angiogenesis resulting in inhibition of endothelial/fibroblast cell proliferation in vitro andVEGF-induced permeability as well as angiogenesis in vivo. In contrast, nanogold did not inhibitVEGF-121or epidermal growth factor, two non^heparin-binding growth factors, mediated cell proliferation. Gold nanoparticles significantly inhibited VEGF receptor-2 phosphorylation, intracellular calcium release, and migration and RhoA activation in vitro. These results report for the first time a novel property of gold nanoparticles to bind heparin-binding proteins and thereby inhibit their subsequent signaling events.Angiogenesis, the formation of new blood vessels is essential for the growth and progression of tumors (1, 2). This process is also important for the promotion and maintenance of other diseases like neoplasia and rheumatoid arthritis (3). As there are several reports that indicate that gold salts can retard the progression of rheumatoid arthritis (4), we reasoned that gold nanoparticles might also inhibit angiogenesis. Because vascular endothelial growth factor/vascular permeability factor (VEGF/ VPF; refs. 5, 6) and basic fibroblast growth factor (bFGF; ref. 7) are two critical cytokines for the induction of angiogenesis, we investigated whether nontoxic novel gold nanoparticles (8) being used at present in several biomedical applications could inhibit the functions of these two important proangiogenic growth factors.Here, we report for the first time that nanogold binds to heparin-binding growth factors like VEGF165 and bFGF and inhibit their activity, whereas it does not inhibit the activity of non -heparin-binding growth factors like VEGF121 and endothelial growth factor (EGF). We have found excellent correlation between our in vitro results and in vivo mouse ear and mouse ovarian tumor model systems, where VEGF/VPFinduced permeability was inhibited by nanogold.

The neurotransmitter dopamine (DA) is an important molecule bridging the nervous and immune systems. DA through autocrine/paracrine manner modulates the functions of immune effector cells by acting through its receptors present in these cells. DA also has unique and opposite effects on T cell functions. Although DA activates naïve or resting T cells, but it inhibits activated T cells. In addition, changes in the expression of DA receptors and their signaling pathways especially in T cells are associated with altered immune functions in disorders like schizophrenia and Parkinson's disease. These results suggest an immunoregulatory role of DA. Therefore targeting DA receptors and their signaling pathways in these cells by using DA receptor agonists and antagonists may be useful for the treatment of diseases where DA induced altered immunity play a pathogenic role.