Abstract 1298: Adipocytes Produce The Angiogenesis Inhibitor, Soluble Fms-like Tyrosine Kinase (sflt-1)

Abstract

Vascular endothelial growth factor (VEGF) exerts its effects via receptors, including Flt-1. sFLT-1 is a soluble splice variant that binds VEGF locally so that the molecule cannot signal; sFLT-1 is implicated in preeclampsia, a condition associated with obesity. Adipose tissue has a dense vascular network regulated in part by LYVE-1-expressing macrophages and VEGF. The role of sFLT-1 in adipose tissue angiogenesis has not been investigated. We used RT-PCR and found that sFlt-1 was 2.6-fold upregulated in adipose tissue from preeclamptic women, 2.5-fold in decidua, and 6.9-fold in placenta. Circulating sFlt-1 was 2.4-fold elevated (all compared to pregnant nonpreeclamptic controls; p<0.05). We next cultured human preadi-pocytes and adipocytes to examine sFlt-1 and VEGF. sFlt-1 expression increased 9-fold as preadipocytes matured to adipocytes. Adipocytes actively secreted sFlt-1 into the supernatant. Hypoxia (O2 tension reduced to 3%) did not alter sFlt-1 mRNA, while VEGF expression increased 4-fold. Tumor necrosis factor (TNF)- α (100 ng/ml, 48 h) induced VEGF 2-fold, but reduced sFlt-1 production 4-fold. Angiotensin II, insulin, hydrocortisone, pioglitazone, and 17β-estradiol all had no influcence on adipocyte sFlt-1 expression. In fat tissue biopsies from 69 postmenopausal women, sFlt-1 correlated inversely with BMI (r=-0.36, p=0.002), but directly with adiponectin expression (r=0.33, p=0.01). No significant correlation was found to blood pressure, insulin, or microalbuminuria. Our study shows that sFlt-1 is elevated in the circulation, placenta, and is upregulated in adipose tissue from preeclamptic women. sFlt-1 is expressed and secreted by adipocytes. sFlt-1 is elevated during fat cell differentiation and downregulated by TNF-α. In healthy postmeonopausal women, adipose tissue sFlt-1 correlates with low BMI and high adiponectin expression. We speculate that secreted sFlt-1 from adipocytes may contribute to the vascular damage during preeclampsia. Furthermore, sFlt-1 may play a regulatory role in adipose tissue under other circumstances, perhaps as an angiogenesis regulating factor.