Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis
Paracrine regulation of angiogenesis and adipocyte differentiation during in vivo adipogenesis
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DOI：
10.1161/01.res.0000099243.20096.fa
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发表时间：
2003-10-31
影响因子：
20.1
通讯作者：
Jain, RK
中科院分区：
文献类型：
--
作者：
Fukumura, D;Ushiyama, A;Jain, RK
随着全球肥胖症发病率的增加，需要合理的策略来控制脂肪生成。任何组织的生长都需要功能性和成熟的脉管系统的形成。为了深入了解活跃的脂肪生成和血管生成之间的联系，我们开发了一种模型，使用活体显微镜观察血管生成和脂肪生成的非侵入性和真实的时间。植入的小鼠前脂肪细胞诱导了强烈的血管生成，并在小鼠背部皮褶室形成脂肪垫。新形成的血管随后重塑成由小动脉、毛细血管和小静脉组成的成熟网络，而前脂肪细胞分化成脂肪细胞，如通过aP 2表达增加所证实的。通过用过氧化物酶体增殖物激活受体γ显性负性构建体转染前脂肪细胞来抑制脂肪细胞分化，不仅废除了脂肪组织形成，而且减少了血管生成。令人惊讶的是，血管内皮生长因子受体-2（VEGFR 2）阻断抗体对血管生成的抑制不仅减少了血管生成和组织生长，而且抑制了前脂肪细胞分化。我们发现，这种抑制部分源于内皮细胞和前脂肪细胞之间的旁分泌相互作用，并且内皮细胞中的VEGF-VEGFR 2信号而不是前脂肪细胞介导了这一过程。这些发现揭示了脂肪形成和血管生成的相互调节，并表明阻断VEGF信号传导可以抑制体内脂肪组织形成。
With an increasing incidence of obesity worldwide, rational strategies are needed to control adipogenesis. Growth of any tissue requires the formation of a functional and mature vasculature. To gain mechanistic insight into the link between active adipogenesis and angiogenesis, we developed a model to visualize noninvasively and in real time both angiogenesis and adipogenesis using intravital microscopy. Implanted murine preadipocytes induced vigorous angiogenesis and formed fat pads in a mouse dorsal skin-fold chamber. The newly formed vessels subsequently remodeled into a mature network consisting of arterioles, capillaries, and venules, whereas the preadipocytes differentiated into adipocytes as confirmed by increased aP2 expression. Inhibition of adipocyte differentiation by transfection of preadipocytes with a peroxisome proliferator-activated receptor gamma dominant-negative construct not only abrogated fat tissue formation but also reduced angiogenesis. Surprisingly, inhibition of angiogenesis by vascular endothelial growth factor receptor-2 (VEGFR2) blocking antibody not only reduced angiogenesis and tissue growth but also inhibited preadipocyte differentiation. We found that part of this inhibition stems from the paracrine interaction between endothelial cells and preadipocytes and that VEGF-VEGFR2 signaling in endothelial cells, but not preadipocytes, mediates this process. These findings reveal a reciprocal regulation of adipogenesis and angiogenesis, and suggest that blockade of VEGF signaling can inhibit in vivo adipose tissue formation.