Abstract
Neovascularization restores blood flow recovery after ischemia in peripheral arterial disease. The main two components of neovascularization are angiogenesis and arteriogenesis. Both of these processes contribute to functional improvements of blood flow after occlusion. However, discriminating between the specific contribution of each process is difficult. A frequently used model for investigating neovascularization is the murine hind limb ischemia model (HLI). With this model, it is difficult to determine the role of angiogenesis, because usually the timing for the sacrifice of the mice is chosen to be optimal for the analysis of arteriogenesis. More importantly, the occurring angiogenesis in the distal calf muscles is probably affected by the proximally occurring arteriogenesis. Therefore, to understand and subsequently intervene in the process of angiogenesis, a model is needed which investigates angiogenesis without the influence of arteriogenesis. In this study we evaluated the in vivo Matrigel plug assay in genetic deficient mice to investigate angiogenesis. Mice deficient for interferon regulatory factor (IRF)3, IRF7, RadioProtective 105 (RP105), Chemokine CC receptor CCR7, and p300/CBP-associated factor (PCAF) underwent the in vivo Matrigel model. Histological analysis of the Matrigel plugs showed an increased angiogenesis in mice deficient of IRF3, IRF7, and RP105, and a decreased angiogenesis in PCAF deficient mice. Our results also suggest an involvement of CCR7 in angiogenesis. Comparing our results with results of the HLI model found in the literature suggests that the in vivo Matrigel plug assay is superior in evaluating the angiogenic response after ischemia.
Highlights
The introduction of peripheral arterial disease (PAD) is a result of narrowing and frequently occlusion of the peripheral arteries by atherosclerotic plaque progression, which leads to impaired blood flow and subsequently ischemia in the tissue
This leads to the conclusion that angiogenesis was increased in the IRF3 deficient mice, IRF3 leads to decreasing angiogenesis
These results support the predictions made in the literature, as IRF3 deficiency probably leads to increased angiogenesis through reduced production of type I IFNs
Summary
The introduction of peripheral arterial disease (PAD) is a result of narrowing and frequently occlusion of the peripheral arteries by atherosclerotic plaque progression, which leads to impaired blood flow and subsequently ischemia in the tissue. The impaired blood flow leads to intermittent claudication and, in more severe stages when occlusion occurs, to critical limb ischemia (CLI). Current therapies for PAD are exercise rehabilitation and in severe cases endovascular revascularization or bypass surgery. Therapeutic neovascularization is a promising technique that has the potential to become an addition to conventional therapies [2]. Neovascularization is the natural mechanism that restores blood flow and recovers tissue perfusion after ischemia. The main two components of neovascularization are angiogenesis and arteriogenesis, both these mechanisms are essential for the restoration of blood flow after arterial occlusions. Identifying mediators that influence neovascularization may lead to discovering targets that can be utilized as therapeutic targets
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