Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells

Abstract

Fatty acid binding protein 4 (FABP4) plays an important role in maintaining glucose and lipid homeostasis. FABP4 has been primarily regarded as an adipocyte- and macrophage-specific protein, but recent studies suggest that it may be more widely expressed. We found strong FABP4 expression in the endothelial cells (ECs) of capillaries and small veins in several mouse and human tissues, including the heart and kidney. FABP4 was also detected in the ECs of mature human placental vessels and infantile hemangiomas, the most common tumor of infancy and ECs. In most of these cases, FABP4 was detected in both the nucleus and cytoplasm. FABP4 mRNA and protein levels were significantly induced in cultured ECs by VEGF-A and bFGF treatment. The effect of VEGF-A on FABP4 expression was inhibited by chemical inhibition or short-hairpin (sh) RNA-mediated knockdown of VEGF-receptor-2 (R2), whereas the VEGFR1 agonists, placental growth factors 1 and 2, had no effect on FABP4 expression. Knockdown of FABP4 in ECs significantly reduced proliferation both under baseline conditions and in response to VEGF and bFGF. Thus, FABP4 emerged as a novel target of the VEGF/VEGFR2 pathway and a positive regulator of cell proliferation in ECs.

Ectopic Fatty Acid–Binding Protein 4 Expression in the Vascular Endothelium is Involved in Neointima Formation After Vascular Injury

“…Gene (Figure 2A) and protein (Figure 2B) expressions of FABP4 were induced by treatment of HCAECs with VEGF and H 2 O 2 as previously reported in endothelial cells 29, 37. Adenovirus‐mediated Fabp4 overexpression in HCAECs (Figure 2C) resulted in efficient gene and protein induction of FABP4 (Figure 2D and 2E) and decreased phosphorylation of NOS3 by stimulation with insulin or VEGF (Figure 2F).…”

“…The present study showed that secretion of FABP4 from endothelial cells was slightly, but significantly, enhanced by stimulation of isoproterenol, similar to that in the case of adipocytes. It was previously shown that treatment with several inflammatory stimuli, including VEGF, H 2 O 2 and cytokines, and cellular senescence induce expression of FABP4 in endothelial cells,29, 37 although the expression level of FABP4 in endothelial cells is lower than that in adipocytes 7, 30. It is possible that the level of FABP4 secreted from endothelial cells is sufficient for causing significant effects on nearby vascular endothelial cells and smooth muscle cells, leading to an inflammatory response, proliferation, and migration from the media into the intima.…”

“…Other than adipocytes and macrophages, FABP4 is also expressed in endothelial cells of capillaries and small veins, but not arteries, in several mouse and human tissues including the heart and kidney 29, 30. We previously demonstrated that ectopic FABP4 expression in endothelial cells of the glomerulus is associated with progression of proteinuria and renal dysfunction31 and that urinary excretion of FABP4 would be a novel biomarker of glomerular damage 32.…”

Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?

“…Afabp mRNA expression and AFABP protein synthesis are significantly induced in cultured endothelial cells by vascular endothelial growth factor (VEGF). Interestingly, knockdown of AFABP has been reported to dramatically reduce proliferation of endothelial cells both under baseline conditions and in response to VEGF in vitro [5]. The same group has identified AFABP as a mediator of angiogenesis [58].…”

“…AFABP accounts for up to 6% of total cytosolic protein in cultured differentiated fat cells [3]. In addition to production in adipocytes, AFABP is also produced in significant amounts in macrophages [4] and endothelial cells [5].…”