Inhibition of protein kinase C enhances angiogenesis induced by platelet-derived growth factor C in hyperglycemic endothelial cells

Abstract

BackgroundDiabetes is a risk factor for the development of cardiovascular diseases with impaired angiogenesis. We have previously shown that platelet-derived growth factor C (PDGF-C) and its receptor, PDGF receptor α (PDGFR-α) were downregulated in ischemic limbs of diabetic mice, although the underlying mechanisms remained elusive. Protein kinase C (PKC) is a family of serine/threonine kinases and is known to be involved in angiogenesis. The purpose of this study is to elucidate the mechanisms of how PDGF-C/PDGFR-α axis is impaired in diabetes.MethodsHuman umbilical vein endothelial cells (HUVECs) and human cardiac microvascular endothelial cells (HMVECs) cultured in normoglycemic or hyperglycemic conditions were examined. We also examined the effects of PKC inhibition on the PDGF-C/PDGFR-α axis in endothelial cells exposed to hyperglycemia.ResultsHyperglycemia inhibited proliferation and decreased viability of both HUVECs and HMVECs. Hyperglycemic endothelial cells exhibited decreased PDGFR-α expression both at messenger RNA (mRNA) and protein levels, while there was no significant change in expression of PDGF-C. We also found that expression of PKC-α, one of the PKC isoforms, was increased in hyperglycemic endothelial cells and that inhibition of PKC upregulated PDGFR-α expression in these cells. Phosphorylation of extracellular signal-regulated kinase (ERK) and Akt induced by PDGF-C was significantly attenuated in hyperglycemic endothelial cells, whereas inhibition of PKC effectively reversed these inhibitory effects. Moreover, inhibition of PKC also promoted angiogenesis induced by PDGF-C in hyperglycemic endothelial cells, which was not observed in vascular endothelial growth factor-A (VEGF-A)-induced angiogenesis.ConclusionsThese findings suggest that downregulation of the PDGF-C/PDGFR-α axis is involved in impaired angiogenesis of hyperglycemia through upregulation of PKC. Targeting PKC to restore PDGF-C signaling might be a novel therapeutic strategy for the treatment of vascular complications in diabetes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0180-9) contains supplementary material, which is available to authorized users.

Human chorionic villous mesenchymal stem/stromal cells protect endothelial cells from injury induced by high level of glucose

“…8b ). Importantly, CMpMSC reversed the anti-angiogenic effect of glucose [ 20 ] on endothelial cells (Fig. 8d, e ).…”

“…3d – f ). This inhibitory effect of glucose on endothelial cell proliferation [ 19 , 20 ] was reversed by pMSCs (Fig. 4a – c ).…”

“…CMpMSC and ICpMSC reduced endothelial cell expression of antiproliferative genes including CAV1 [ 21 ] and COL18A1 [ 22 ] (Tables 2 and 5 ). In addition, ICpMSC induced endothelial cell expression of pro-proliferative genes including PLAT [ 20 ] and PDGFRA [ 23 ] (Table 5 ). This protective role of pMSCs was further confirmed by the ability of CMpMSC to reverse the inhibitory effect of glucose on endothelial cell migration [ 24 ] (Fig.…”

Antiangiogenic compounds: well-established drugs versus emerging natural molecules

“…PKC is also known to be involved in RTKs-mediated angiogenesis signaling pathways, and its inhibition was shown to promote angiogenesis. The inhibition of PKC is thus regarded as a novel strategy for therapeutic angiogenesis, in cases of ischemic cardiovascular diseases [103].…”

Downregulation of miR‑146a promotes proliferation and migration of AOB‑treated embryoid body via PDGFRA induction

“…Platelet-derived growth factor receptor alpha (PDGFRA) is identified as a functional gene that is restrictedly expressed during in vitro differentiation and mouse embryogenesis (4). PDGFRA expression is evident in undifferentiated mouse embryonic stem cells (ESCs), at sites of blood island formation and vasculogenesis during early embryogenesis, as well as during angiogenesis in the adult mice (5). MicroRNAs (miRNAs/miRs) are non-coding single-stranded RNAs that can bind to the 3'-untranslated regions of target mRNAs, leading to their translation or degradation (6,7).…”