Enhanced angiogenesis in obesity and in response to PPARγ activators through adipocyte VEGF and ANGPTL4 production
Enhanced angiogenesis in obesity and in response to PPARγ activators through adipocyte VEGF and ANGPTL4 production
复制标题
DOI：
10.1152/ajpendo.90345.2008
复制
发表时间：
2008-11-01
影响因子：
5.1
通讯作者：
Corvera, Silvia
中科院分区：
文献类型：
--
作者：
Gealekman, Olga;Burkart, Alison;Corvera, Silvia
[10]杨文，李文.通过脂肪细胞VEGF和ANGPTL 4的产生增强肥胖症中的血管生成和对PPAR γ激活剂的反应。Am J Physiol Endocrinol Metab 295：E1056-E1064，2008.首次发表于2008年8月26日; doi：10.1152/ajpendo.90345.2008。PPAR γ激活剂如罗格列酮（RSG）刺激脂肪细胞分化并增加皮下脂肪组织质量。然而，除了前脂肪细胞分化，脂肪组织扩张需要新血管形成来支持增加的脂肪细胞数量。有趣的是，内皮细胞的生长和分化在体外被RSG有效地抑制，提出了这种药物如何在抑制血管生成的同时诱导脂肪组织质量增加的问题。我们发现用RSG处理的小鼠的脂肪组织具有增加的毛细血管密度。为了确定RSG是否刺激脂肪组织血管生成，我们开发了一种新的测定来研究离体血管生成芽的形成。同样大小的脂肪组织碎片，但不是从主动脉环，血管生成芽的形成大大增加了肥胖和TZD治疗在体内。为了确定在RSG刺激的脂肪组织中的血管生成所涉及的机制，检查了脂肪细胞的促血管生成因子的表达。RSG体内处理刺激了VEGFA和VEGFB以及血管生成素样因子-4（ANGPTL 4）的表达。为了确定这些因素的潜在作用，我们分析了它们在体外对内皮细胞生长和分化的影响。我们发现ANGPTL 4刺激内皮细胞生长和小管形成，尽管比VEGF更弱。然而，ANGPTL 4在VEGF存在或不存在的情况下减轻RSG对内皮细胞的生长抑制作用。因此，VEGF和ANGPTL 4之间的相互作用可能导致脂肪组织毛细血管网络的净扩张，这是脂肪组织生长所需的，响应于PPAR γ激活剂。
Gealekman O, Burkart A, Chouinard M, Nicoloro SM, Straubhaar J, Corvera S. Enhanced angiogenesis in obesity and in response to PPAR gamma activators through adipocyte VEGF and ANGPTL4 production. Am J Physiol Endocrinol Metab 295: E1056-E1064, 2008. First published August 26, 2008; doi:10.1152/ajpendo.90345.2008.-PPAR gamma activators such as rosiglitazone (RSG) stimulate adipocyte differentiation and increase subcutaneous adipose tissue mass. However, in addition to preadipocyte differentiation, adipose tissue expansion requires neovascularization to support increased adipocyte numbers. Paradoxically, endothelial cell growth and differentiation is potently inhibited by RSG in vitro, raising the question of how this drug can induce an increase in adipose tissue mass while inhibiting angiogenesis. We find that adipose tissue from mice treated with RSG have increased capillary density. To determine whether adipose tissue angiogenesis was stimulated by RSG, we developed a novel assay to study angiogenic sprout formation ex vivo. Angiogenic sprout formation from equally sized adipose tissue fragments, but not from aorta rings, was greatly increased by obesity and by TZD treatment in vivo. To define the mechanism involved in RSG-stimulated angiogenesis in adipose tissue, the expression of proangiogenic factors by adipocytes was examined. Expression of VEGFA and VEGFB, as well as of the angiopoietin-like factor-4 (ANGPTL4), was stimulated by in vivo treatment with RSG. To define the potential role of these factors, we analyzed their effects on endothelial cell growth and differentiation in vitro. We found that ANGPTL4 stimulates endothelial cell growth and tubule formation, albeit more weakly than VEGF. However, ANGPTL4 mitigates the growth inhibitory actions of RSG on endothelial cells in the presence or absence of VEGF. Thus, the interplay between VEGF and ANGPTL4 could lead to a net expansion of the adipose tissue capillary network, required for adipose tissue growth, in response to PPAR gamma activators.