Abstract
Diabetic foot disease (DFD) is a common and serious complication for diabetes and is characterized with impaired angiogenesis. In addition to the well-defined role of vascular endothelial growth factor (VEGF) -A and its defect in the pathogenesis of DFD, another VEGF family member, placental growth factor (PlGF), was also recently found to alter expression pattern in the DFD patients with undetermined mechanisms. This question was thus addressed in the current study. We detected attenuated PlGF upregulation in a mouse DFD model. In addition, the major cell types at the wound to express the unique PlGF receptor, VEGF receptor 1 (VEGFR1), were macrophages and endothelial cells. To assess how PlGF regulates DFD-associated angiogenesis, we injected recombinant PlGF and depleted VEGF1R specifically in macrophages by local injection of an adeno-associated virus (AAV) carrying siRNA for VEGFR1 under a macrophage-specific CD68 promoter. We found that the angiogenesis and recovery of the DFD were both improved by PlGF injection. The PlGF-induced improvement in angiogenesis and the recovery of skin injury were largely attenuated by macrophage-specific depletion of VEGF1R, likely resulting from reduced macrophage number and reduced M2 polarization. Together, our data suggest that reduced PlGF compromises angiogenesis in DFD at least partially through macrophages.
Highlights
Vascular endothelial growth factor -A (VEGF-A), a potent endothelial cell mitogen, has been shown to play a substantial role in angiogenesis [1]
Since we found that placental growth factor (PlGF)-induced improvement in angiogenesis and recovery of Diabetic foot disease (DFD) was largely attenuated by macrophagespecific depletion of VEGF1R, we examined the changes in macrophages in response to PlGF and VEGF receptor 1 (VEGFR1) depletion
The interaction between endothelial cells and macrophages alters the phenotypes of each other to allow the oxygen and nutrient transit from circulation to promote cell proliferation and differentiation, and the production and release of growth factors like proangiogenic factors from macrophages to affect the formation of new capillaries through angiogenesis [30]
Summary
Vascular endothelial growth factor -A (VEGF-A), a potent endothelial cell mitogen, has been shown to play a substantial role in angiogenesis [1]. Besides VEGFA, VEGF family has 5 other members, among which placental growth factor (PlGF) is a critical one and has been shown to be associated with pathological angiogenesis [3]. We have shown that PlGF plays a critical role in gestational beta-cell growth [11], likely as a potent growth factor that regulates the crosstalk between trophic macrophages and pancreatic beta-cells [11]. In another study that investigated the role of PlGF in diabetic wound healing, the effects of PlGF on fibroblasts but not on macrophages were investigated [14]. Since the major cell types that harbor the unique PlGF receptor VEGFR1 are macrophages, endothelial cells and fibroblasts [2], the exact molecular mechanisms underlying PlGF-regulated angiogenesis in DFD seems warrant further investigation, which was addressed in the current study
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