Endothelial cell-fatty acid binding protein 4 promotes angiogenesis: role of stem cell factor/c-kit pathway

Abstract

Fatty acid binding protein 4 (FABP4) plays an important role in regulation of glucose and lipid homeostasis as well as inflammation through its actions in adipocytes and macrophages. FABP4 is also expressed in a subset of endothelial cells, but its role in this cell type is not known. We found that FABP4-deficient human umbilical vein endothelial cells (HUVECs) demonstrate a markedly increased susceptibility to apoptosis as well as decreased migration and capillary network formation. Aortic rings from FABP4−/− mice demonstrated decreased angiogenic sprouting, which was recovered by reconstitution of FABP4. FABP4 was strongly regulated by mTORC1 and inhibited by Rapamycin. FABP4 modulated activation of several important signaling pathways in HUVECs, including downregulation of P38, eNOS, and stem cell factor (SCF)/c-kit signaling. Of these, the SCF/c-kit pathway was found to have a major role in attenuated angiogenic activity of FABP4-deficient ECs as provision of exogenous SCF resulted in a significant recovery in cell proliferation, survival, morphogenesis, and aortic ring sprouting. These data unravel a novel pro-angiogenic role for endothelial cell-FABP4 and suggest that it could be exploited as a potential target for diseases associated with pathological angiogenesis.

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

“…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]. Thus, AFABP-deficient human umbilical vein endothelial cells demonstrate a markedly increased susceptibility to apoptosis, as well as decreased migration and capillary network formation [58].…”

“…Thus, AFABP-deficient human umbilical vein endothelial cells demonstrate a markedly increased susceptibility to apoptosis, as well as decreased migration and capillary network formation [58]. Furthermore, aortic rings from Afabp −/− mice show decreased angiogenic sprouting, which is reversible upon Afabp re-expression [58].…”

High‐methionine diets accelerate atherosclerosis by HHcy‐mediated FABP4 gene demethylation pathway via DNMT1 in ApoE−/− mice

“…Overexpression of FABP4 facilitates foam cell formation in THP-1 macrophages, and enhances the accumulation of cholesterols and triglycerides [15,16]. Hcy suppresses adipogenesis in 3T3-L1 preadipocytes by decreasing lipid accumulation and downregulating gene expression of adipocyte protein 2 and peroxisome proliferator-activated receptor gamma (PPAR-gamma) [17].…”

Manipulating Angiogenesis by Targeting Endothelial Metabolism: Hitting the Engine Rather than the Drivers—A New Perspective?

“…Carnitine palmitoyltransferases (CPTs), more precisely CPT1, catalyze the transesterification of long-chain FA-CoA to acyl-L-carnitine and its transport into the intramitochondrial matrix where acyl-L-carnitine is then converted back to acyl-CoA by CPT2 (Kopec and Fritz, 1973;Kerner and Hoppel, 2000). (Elmasri et al, 2009(Elmasri et al, , 2012. FABP4 is also a target of NICD, which together with FOXO1 activates FABP4 transcription (Harjes et al, 2014).…”