Anti-Angiogenic Mechanisms in Human Obesity

描述（由申请人提供）：肥胖已成为美国最严重的医疗保健问题之一，因为69%的美国人口目前超重或肥胖。脂肪组织功能障碍是肥胖与心脏代谢疾病发病机制的重要标志，我们小组先前的工作已经证明脂肪组织的定性性质形成全身表型。特别是，肥胖症中脂肪组织血管生成受损与炎症和代谢功能障碍有关;然而，致病机制尚未完全了解。我们描述了一种新的内源性血管内皮生长因子（VEGF-A）亚型，VEGF-A165 b，它在肥胖症中选择性过表达并抑制血管生成。我们的初步数据表明，Wnt 5a信号系统的扰动上调VEGF-A165 b的肥胖条件下，减肥手术减肥修改。在目标1中，我们将检查150名肥胖和50名瘦受试者活检脂肪样本中脂肪库特异性微血管血管生成反应。我们将描述VEGF-A亚型与血管生成能力和血管形成的关系。我们假设抑制性同种型VEGF-A165 b在肥胖症中上调，与脂肪中的抗血管生成作用相关，并与全身代谢功能障碍有关。在目标2中，将使用从目标1获得的人脂肪组织样品采用Wnt信号传导的特异性抑制剂，以提供用于理解VEGF-A 165 b表达调控的分子框架。在目标3中，我们将在目标1中相同的150名肥胖受试者中，在减肥手术后6个月重新检查脂肪血管生成能力和VEGF亚型表达。我们将测试目标2中明确确定的相关分子途径是否受到体重减轻的影响。我们试图确定新的决定因素的脂肪组织生物学和血管生成的代谢变化，这将发展与显着的体重减轻肥胖的个人。我们的建议可以确定Wnt 5a-VEGF-A165 b轴作为血管生成，脂肪组织生物学，因此，全身性疾病的临床肥胖症的一种新的调节剂，并可能导致新的治疗靶点的鉴定。

DESCRIPTION (provided by applicant): Obesity has emerged as one of the most critical health care problems in the US as 69% of the US population is currently overweight or obese. Adipose tissue dysfunction is an essential hallmark linking obesity to the pathogenesis of cardiometabolic disease, and prior work form our group has demonstrated that qualitative properties of adipose tissue shape systemic phenotypes. In particular, impaired adipose tissue angiogenesis in obesity has been associated with inflammation and metabolic dysfunction; however pathogenic mechanisms are incompletely understood. We describe a novel endogenous isoform of vascular endothelial growth factor (VEGF-A), VEGF-A165b that is selectively over-expressed in obesity and inhibits angiogenesis. Our preliminary data suggest that perturbations in the Wnt5a signaling system up-regulates VEGF-A165b under conditions of obesity that is modified by bariatric surgical weight loss. In aim 1, we will examine adipose depot-specific microvascular angiogenic responses in biopsied fat samples from 150 obese and 50 lean subjects. We will characterize VEGF-A isoforms in relation to angiogenic capacity and vascularization. We hypothesize that inhibitory isoform VEGF-A165b will be up- regulated in obesity, associated with anti-angiogenic actions in fat, and relate to whole body metabolic dysfunction. In aim 2, specific inhibitors of Wnt signaling will be employed using human adipose tissue samples secured from aim 1 to provide a molecular framework for understanding the regulation of VEGF-A 165b expression. In aim 3, we will re-examine adipose angiogenic capacity and VEGF isoform expression at 6 months following bariatric surgery in the same 150 obese subjects from aim 1. We will test whether relevant molecular pathways specifically identified in aim 2 are influenced by weight reduction. We seek to identify novel determinants of adipose tissue biology and angiogenesis in relation to metabolic changes which will develop in association with marked weight loss in obese individuals. Our proposal may identify the Wnt5a-VEGF-A 165b axis as a novel modulator of angiogenesis, adipose tissue biology, and consequently, systemic disease in clinical obesity and potentially lead to the identification of new therapeutic targets.