MAPK/ERK signalling mediates VEGF‐induced bone marrow stem cell differentiation into endothelial cell

Abstract

Multi-potent adult progenitor cells (MAPCs) differentiate into endothelial cells (ECs) in the presence of vascular endothelial growth factor (VEGF). The mechanism(s) of VEGF-induced differentiation of MAPCs to ECs are not yet known. We, therefore, examined the role of mitogen-activated protein kinase/extracellular signal-regulated kinase (p42/44-MAPK/ERK1/2) signalling in endothelial differentiation from bone marrow stem cells. We observed that VEGF stimulation of MAPCs for 14 days results in a significant expression of endothelial-specific gene and/or proteins including von Willebrand factor (vWF), vascular endothelial-cadherin (VE-cadherin), VEGF receptor-2 (VEGFR2), and CD31. Up-regulation of EC-specific markers was accompanied by a cobblestone morphology, expression of endothelial nitric oxide synthase (eNOS), and Dil-Ac-LDL uptake, typical for EC morphology and function. VEGF induced a sustained activation of p42 MAPK/ERK, but not that of p44 MAPK/ERK during the course of MAPCs differentiation in a time-dependent manner up to 14 days. VEGF-induced activation of p42 MAPK/ERK also led to the nuclear translocation of MAPK/ERK1/2. Incubation of MAPCs with MAPK/ERK1/2 phosphorylation inhibitor PD98059 blocked the sustained VEGF-induced MAPK/ERK1/2 phosphorylation as well as its nuclear translocation in the differentiating MAPCs. Inhibition of MAPK/ERK1/2 phosphorylation by PD98059 also blocked the expression of EC-specific genes in these cells and their differentiation to ECs. These data suggest that VEGF induces MAPC differentiation into EC via a. MAPK/ERK1/2 signalling pathway-mediated mechanism in vitro.

VEGF-A not Ang2 mediates endothelial-like differentiation of immature DCs by ERK1/2 signaling in the microenvironment of human colon adenocarcinoma

“…In this study, we observed that a sustained activation of the ERK1/2 is required for endothelial-like differentiation of iDCs. It is established that the nuclear translocation of phosphorylated ERK is key to the differentiation of various cells (14,15,30). our results demonstrated that activated ERK1/2 was present in the nucleus of cells incubated with SW620 supernatant.…”

“…The ERK1/2 signaling plays a key role in mediating signals from membrane receptors to the nucleus, and is involved in the processes of cell growth, differentiation, proliferation and apoptosis (28,29). A study has shown that the ERK pathway plays a central role in VEGF-induced bone marrow stem cell differentiation into ECs (15). In this study, we observed that a sustained activation of the ERK1/2 is required for endothelial-like differentiation of iDCs.…”

“…The nuclear translocation of phosphorylation of ERK1/2 is key to activate related transcription factors to lead to cell differentiation (14,15). Before the induction by SW620 supernatant, the level of phospho-ERK1/2 (green) in iDCs was low (Fig.…”

Molecular mechanism of inhibition of the abnormal proliferation of human umbilical vein endothelial cells by hydroxysafflor-yellow A

“…Subsequently, PI3K activation activates PKC, which is followed by the activation of MAPKKK and MAPK pathway-signalling molecules (Rask-Madsen & King 2008). Most researchers believed that VEGF induces phosphorylation of Ras-GTP in endothelial cells, and that activated Ras activates Raf-MEK-ERK, which is a signalling pathway required by in vitro cultured HUVEC during the migration, proliferation and formation of new blood vessels (the Ras Raf MEK ERK-activated MAPK pathway) (Xu et al 2008). Other investigators believe that after binding VEGF and VEGFR-2, MAPK signal transduction is activated through the PLC-g PKC pathway (Grothey & Ellis 2008).…”

Activation of interleukin-6-induced glycoprotein 130/signal transducer and activator of transcription 3 pathway in mesenchymal stem cells enhances hepatic differentiation, proliferation, and liver regeneration

“…6,7,28 Potential candidates include hepatocyte growth factor, epidermal growth factor, oncostatin M, and vascular endothelial growth factor, and these factors were therefore nominated as modulators of stem cell differentiation. 5,[29][30][31] However, the length of time required during hepatic differentiation of MSCs under prolonged exposure in the specific culture media is the major drawback. On average, the expression of hepatic-specific genes in MSCs were detectable by culturing in growth factor-enriched medium for more than 1 week.…”