Fukumura Dai, Ushiyama Akira, Duda Dan G, Xu Lei, Tam Joshua, Krishna V, Chatterjee K, Garkavtsev Igor, Jain Rakesh K
Edwin L. Steele Laboratory, Massachusetts General Hospital and Harvard Medical School, Boston, Mass 02114, USA.
Circ Res. 2003 Oct 31;93(9):e88-97. doi: 10.1161/01.RES.0000099243.20096.FA. Epub 2003 Oct 2.
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. The full text of this article is available online at http://www.circresaha.org.
随着全球肥胖症发病率的不断上升，需要合理的策略来控制脂肪生成。任何组织的生长都需要形成功能性和成熟的脉管系统。为了深入了解活跃的脂肪生成与血管生成之间的联系，我们开发了一种模型，利用活体显微镜对血管生成和脂肪生成进行非侵入性实时可视化。植入的小鼠前脂肪细胞在小鼠背部皮肤褶皱腔室中诱导强烈的血管生成并形成脂肪垫。新形成的血管随后重塑为一个由小动脉、毛细血管和小静脉组成的成熟网络，而前脂肪细胞分化为脂肪细胞，这通过aP2表达增加得到证实。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，不仅消除了脂肪组织的形成，还减少了血管生成。令人惊讶的是，用血管内皮生长因子受体-2（VEGFR2）阻断抗体抑制血管生成，不仅减少了血管生成和组织生长，还抑制了前脂肪细胞的分化。我们发现这种抑制部分源于内皮细胞与前脂肪细胞之间的旁分泌相互作用，并且内皮细胞而非前脂肪细胞中的VEGF-VEGFR2信号传导介导了这一过程。这些发现揭示了脂肪生成与血管生成之间的相互调节，并表明阻断VEGF信号传导可以抑制体内脂肪组织的形成。本文的全文可在http://www.circresaha.org在线获取。
