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.
Highlights
There are increasing numbers of patients who suffer from ischemic cardiovascular diseases, and most of such patients have some risk factors
Consistent with this finding, inhibition of Protein kinase C (PKC) led to augmentation of intracellular signaling induced by platelet-derived growth factor C (PDGF-C), resulting in promotion of angiogenesis in hyperglycemic endothelial cells (ECs). These findings suggest that downregulation of the Platelet-derived growth factors (PDGFs)-C/PDGF receptor α (PDGFR-α) axis is involved in impaired angiogenesis of diabetes through upregulation of PKC
We examined two types of human EC; human umbilical vein endothelial cells (HUVECs) and human cardiac microvascular endothelial cells (HMVECs)
Summary
There are increasing numbers of patients who suffer from ischemic cardiovascular diseases, and most of such patients have some risk factors. Therapeutic angiogenesis is a relatively new and promising concept for treating patients with ischemic cardiovascular diseases [8,9,10] It involves the use of angiogenic growth factors to promote development of collateral arteries. It has recently been reported that a ligandindependent VEGF receptor 2 (VEGFR2) signaling pathway is activated in diabetic endothelial cells, leading to impaired responses to exogenous VEGF-A and limited angiogenic events [18,19]. These studies suggest that further basic research is needed to elucidate the mechanisms of angiogenesis, especially in diabetic state, to improve the overall outcome of therapeutic angiogenesis. The purpose of this study is to elucidate the mechanisms of how PDGF-C/PDGFR-α axis is impaired in diabetes
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