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Am J Physiol Endocrinol Metab 294: E336-E344, 2008. First published December 11, 2007; doi:10.1152/ajpendo.00272.2007
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A central role for hepatocyte growth factor in adipose tissue angiogenesis

Lauren N. Bell,1,2 Liying Cai,1,2 Brian H. Johnstone,2 Dmitry O. Traktuev,2 Keith L. March,1,2 and Robert V. Considine1,2,3

1Department of Cellular and Integrative Physiology, 2Indiana Center for Vascular Biology and Medicine, 3Division of Endocrinology and Metabolism, Indiana University School of Medicine, Indianapolis, Indiana

Submitted 1 May 2007 ; accepted in final form 6 December 2007

Hepatocyte growth factor (HGF) is a potent mitogenic and angiogenic factor produced in human adipose tissue. In this study, we use 3T3-F442A preadipocytes to study the contribution of HGF to angiogenesis in an in vivo fat pad development model. As observed for human adipocytes, HGF is synthesized and secreted by 3T3-F442A preadipocytes and mature adipocytes. HGF knockdown with small-interfering RNA reduced HGF mRNA expression 82.3 ± 4.2% and protein secretion 82.9 ± 1.4% from 3T3-F442A preadipocytes. Silencing of HGF resulted in a 70.5 ± 19.0% reduction in endothelial progenitor cell migration to 3T3-F442A-conditioned medium in vitro. 3T3-F442A preadipocytes injected under the skin of mice form a fat pad containing mature, lipid-filled adipocytes and a functional vasculature. At 72 h postinjection, expression of the endothelial cell genes TIE-1 and platelet endothelial cell adhesion molecule (PECAM)-1 was decreased 94.4 ± 2.2 and 91.5 ± 2.5%, respectively, in 3T3-F442A fat pads with HGF silencing. Knockdown of HGF had no effect on differentiation of 3T3-F442A preadipocytes to mature adipocytes in vitro or in vivo. In developing fat pads under the skin of HGF overexpressing transgenic mice, TIE-1 and PECAM-1 mRNA was increased 16.5- and 21.4-fold, respectively, at 72 h postinjection. The increase in gene expression correlated with immunohistochemical evidence of endothelial cell migration in the developing fat pad. These data suggest that HGF has a central role in regulating angiogenesis in adipose tissue.

obesity; neovascularization; 3T3-F442A; tie-1; platelet endothelial cell adhesion molecule-1


Address for reprint requests and other correspondence: R. V. Considine, Indiana Univ. School of Medicine, 541 North Clinical Drive, Clinical Bldg. 455, Indianapolis, IN 46202-5111 (e-mail: rconsidi{at}iupui.edu)






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