Fibroblast Growth Factor-2 Gene Transfer Can Stimulate Hepatocyte Growth Factor Expression Irrespective of Hypoxia-Mediated Downregulation in Ischemic Limbs

Abstract

Abstract-Hepatocyte growth factor (HGF) is a potent angiogenic polypeptide that stimulates angiogenesis. Transcriptional regulation of HGF, however, has not been fully defined, with the exception of the hypoxia-mediated downregulation in cultured cells. In the present study, we report that angiogenic growth factors, including HGF, were upregulated in a murine model of critical limb ischemia in vivo, a finding that was in conflict with previous in vitro data. Mice deficient in basic fibroblast growth factor-2 (FGF-2) showed reduced induction of HGF protein in ischemic muscles, and overexpression of FGF-2 via gene transfer stimulated endogenous HGF, irrespective of the presence of ischemia. In culture, FGF-2 rapidly stimulated HGF mRNA, and a sustained expression was evident in the time course in vascular smooth muscle cells and fibroblasts. FGF-2-mediated induction of HGF was fully dependent on the mitogen-activated protein kinase pathway yet was not affected by either hypoxia or a protein kinase A inhibitor. In the early expression, FGF-2 directly stimulated HGF mRNA without the requirement of new protein synthesis, whereas sustained induction of HGF in the later phase was partly mediated by platelet-derived growth factor-AA. Furthermore, in vivo overexpression of FGF-2 significantly improved the blood perfusion, and the effect was abolished by systemic blockade of HGF in ischemic limbs. This is the first demonstration of a regulational mechanism of HGF expression via FGF-2 that was independent of the presence of hypoxia. The harmonized therapeutic effects of FGF-2, accompanied with the activity of endogenous HGF, may provide a beneficial effect for the treatment of limb ischemia.

Dipalmitoylphosphatidic acid inhibits breast cancer growth by suppressing angiogenesis via inhibition of the CUX1/FGF1/HGF signalling pathway

“…DPPA regulated the differential expression of 4 candidate genes in the array by more than 5‐fold compared to that in the DMSO group (Figure 5A). A report indicated that FGF2 stimulates HGF transcription and protein expression in ischaemic limbs 20. FGF1 and FGF2 are both FGF members that are involved in angiogenesis.…”

Tumor–stromal cell interaction under hypoxia increases the invasiveness of pancreatic cancer cells through the hepatocyte growth factor/c‐Met pathway

“…We also confirmed the induction of HIF-1a expression in MRC5 as well as PK8 cells under hypoxia. Together, it is possible that MMP-2, MMP-7, MT1-MMP and cMet in PK8 cells and HGF in MRC5 cells might be upregulated 29,30 Thus it might be noteworthy aspect that HGF secretion from fibroblasts was stimulated under hypoxia. Although we also speculated that the expression of HGF is possibly regulated by HIF-1a.…”

La résistance aux traitements antiangiogéniques

“…Le FGF jouerait aussi un rôle de régulateur en amont en stimulant l'expression du VEGF dans les cellules endothéliales et celles du stroma. Dans un modèle de muscle ischémié, in vitro et in vivo, il augmente l'expression du HGF (hepatocyte growth factor) [13]. Dans un autre modèle préclinique de cancer de pancréas, on observe, à la suite de l'administration d'anti-VEGF, un pic de FGF plasmatique qui est associé à une néoangiogenèse secondaire [14,15].…”