Non-COX Arachidonic Acid Metabolites and Angiogenesis

组织损伤后的炎症被认为在各种疾病的发生和发展中很重要，包括动脉粥样硬化、癌症和视网膜病变。磷脂酶A2s （PLA2s）是一组分解磷脂生成花生四烯酸和溶血磷脂的酶，与炎症有关。动脉粥样硬化发生的主要原因之一是血管生成。内皮细胞（EC）的迁移和增殖是血管生成的关键事件。越来越多的证据表明，PLA2、花生四烯酸及其类二十烷代谢产物在调节细胞迁移、增殖和凋亡中发挥作用。此外，最近使用非甾体抗炎药的研究揭示了类二十烷在血管生成中的潜在作用。基于此，我们假设类二十烷，特别是花生四烯酸的脂氧合酶-单氧合酶代谢物，在血管生成中起重要作用，从而影响动脉粥样硬化的发病机制。为了测试类二十烷酸在血管生成中的作用，我们将解决以下四个具体目标：1。目的鉴定人微血管内皮细胞（HMVEC）中产生的类二十烷酸，并通过体外和体内模型确定其对血管生成的影响。2. 目的：探讨血管生成类二十烷酸对HMVEC迁移和增殖的影响。3. 检测Jak/STAT和PI3K/Akt通路在血管生成类二十烷酸诱导的HMVEC迁移和增殖中的作用。4. 目的鉴定类二十烷酸诱导血管生成的效应分子，并研究其在HMVEC和血管平滑肌细胞中的表达调控机制。这一建议的结果将为鉴定特定的血管生成类二十烷提供新的信息，并阐明这些脂质分子刺激血管生成的潜在机制。反过来，这些知识可能有助于开发预防动脉粥样硬化等疾病进展的治疗方法。

Inflammation that follows tissue injury is believed to be important in the initiation and progression of various diseases including, atherosclerosis, cancer, and retinopathy. Phospholipase A2s (PLA2s), a group of enzymes that breakdown phospholipids generating arachidonic acid and lysophospholipids have been implicated in inflammation. One of the major events underlying the progression of atherosclerosis is angiogenesis. Endothelial cell (EC) migration and proliferation are critical events in angiogenesis. Emerging evidence suggests that PLA2, arachidonic acid and its eicosanoid metabolites play a role in the regulation of cell migration, proliferation, and apoptosis. In addition, recent investigations using nonsteroidal anti-inflammatory drugs reveal a potential role for eicosanoids in angiogenesis. Based on this knowledge, we hypothesize that eicosanoids, particularly the lipoxygenase-monooxygenase metabolites of arachidonic acid, play an important role in angiogenesis and thereby influence the pathogenesis of atherosclerosis. To test the role of eicosanoids in angiogenesis we will address the following four specific aims: 1. To identify eicosanoids produced in human microvascular endothelial cells (HMVEC) and determine their effects on angiogenesis using in vitro and in vivo models. 2. To determine the effects of angiogenic eicosanoids on HMVEC migration and proliferation. 3. To test the role of the Jak/STAT and PI3K/Akt pathways in angiogenic eicosanoid-induced HMVEC migration and proliferation. 4. To identify the effector molecules of eicosanoid-induced angiogenesis and study the mechanisms underlying their regulation of expression in HMVEC and vascular smooth muscle cells. The results of this proposal will provide novel information on the identification of specific angiogenic eicosanoids and on elucidation of the underlying mechanisms by which these lipid molecules stimulate angiogenesis. Such knowledge, in turn, could be useful in developing therapeutics in the prevention of progression of diseases such as atherosclerosis.