The Neurotransmitter dopamine and angiogenesis

血管生成对于超过最小尺寸的肿瘤生长是必不可少的，在许多其他肿瘤中也是重要的 病理生理状况。人们普遍预期，血管生成的调节(肿瘤中的抑制， 刺激血管功能不全)将提供重要的治疗益处。许多不同的细胞因子和 生长因子表达血管生成活性，其中VPFNEGF因其有效性、选择性而脱颖而出 血管内皮细胞及其在恶性肿瘤和其他临床中的持续过表达 血管生成起重要作用的条件。最近，我们首次描述了 神经递质多巴胺(DA)长期用于帕金森病的治疗 (以及心力衰竭的治疗)和DA D2受体激动剂，有效和选择性地阻断 VPFNEGF诱导的体内血管生成，无论是由肿瘤还是在腺病毒载体诱导 经改造后可表达VPF/VEGF。这里提出的实验旨在研究 DA或其相关化合物抑制VPFNEGF诱导的血管生成的机制细节。在AIM 1，我们将研究G蛋白偶联受体(GPCR)DA D2受体如何影响VEGFR-2 信号通路。通过利用遗传和药理学方法，目标2将重点揭示如何 外周DA可能影响VPFNEGF介导的正常和病理性血管生成。在《目标3》中， 将开展研究，以确定DA及其相关分子作为抗血管生成剂在 肿瘤腹水模型和实体瘤模型。此外，我们将审查DA或相关的 在临床前环境中，化合物可以与其他常规药物(如紫杉醇)一起使用。 此外，还将研究DA在其他血管生成分子介导的血管生成中的作用。 在动物模型中。将利用新生大鼠视网膜的发育性血管生成来测试其效果。 DA在正常生理性血管生成中的作用。综上所述，拟议的研究将得出一个重要的 血管生成和神经系统之间的概念联系，并表明DA，已经在临床上用于 其他用途，可能在抗血管生成治疗中有价值。

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 VPFNEGF 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 VPFNEGF-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 VPFNEGF-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 VPFNEGF. 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.