Abstract
Non-healing ulcers are a serious complication of diabetes mellitus and a major unmet medical need. A major cause for the lack of healing is the impairment of spontaneous vascularization in the skin, despite mostly normal blood flow in deeper large vessels. Therefore, pro-angiogenic treatments are needed to increase therapeutic perfusion by recruiting new arterial connections (therapeutic arteriogenesis). Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis in physiology and disease, but exploitation of its therapeutic potential requires careful control of its dose distribution in tissue. Co-delivery of platelet derived growth factor-BB (PDGF-BB) has been shown to expand the therapeutic window of VEGF and also improve associated arteriogenesis. We used a highly controlled protein delivery system, based on a clinically applicable fibrin-based platform, to investigate the angiogenic and arteriogenic potential of engineered versions (TG-) of VEGF and PDGF-BB proteins in the skin of diabetic and obese db/db mice. Intradermal delivery of therapeutically relevant doses of TG-VEGF and TG-PDGF-BB induced robust growth of new microvascular networks with similar efficacy as in normal littermate control mice. Further, TG-PDGF-BB prevented the formation of aberrant vascular enlargements by high TG-VEGF levels. As fibrin was degraded after the first week, the induced angiogenesis mostly regressed by 4 weeks, but it promoted effective arteriogenesis in the dermal layer. Therefore, controlled co-delivery of TG-VEGF and TG-PDGF-BB recombinant proteins is effective to induce angiogenesis and arteriogenesis in diabetic mouse skin and should be further investigated to promote diabetic wound healing.
Highlights
Diabetes is a global health issue, ranking among the top 10 causes of death globally, and obesity-associated type 2 diabetes is the most prevalent form (Saeedi et al, 2019)
We have previously shown that overexpression of platelet derived growth factor-BB (PDGF-BB) alone is incapable of starting the angiogenic process in vivo in the absence of Vascular endothelial growth factor (VEGF) (Banfi et al, 2012; Gianni-Barrera et al, 2016)
The vessels, which persisted under the TG-VEGF alone and with TG-PDGF-BB co-expression conditions, formed capillary-size micro-vascular networks with a homogeneous size distribution, similar to control samples (Figure 6d,e). These results suggest that transient delivery of both TG-VEGF alone and with TG-PDGF-BB induced a strong angiogenic effect in diabetic mouse skin by 7 days, which was transient and mostly regressed by 4 weeks
Summary
Diabetes is a global health issue, ranking among the top 10 causes of death globally, and obesity-associated type 2 diabetes is the most prevalent form (Saeedi et al, 2019). Diabetic foot ulcers (DFU) are a common secondary complication of diabetes and are caused by inadequate arterial blood flow and/or sensory neuropathy (Tecilazich et al, 2011). DFU show areas of local skin ischemia with severely impaired blood flow (Falanga, 2005; Sharma et al, 2020). Therapeutic angiogenesis, which aims at stimulating neovascularization through local delivery of angiogenic factors to improve the perfusion of ischemic tissue, is an attractive treatment strategy. Vascular endothelial growth factor-A (VEGF) is the master regulator of vascular growth and is the major molecular target for therapeutic angiogenesis (Uccelli et al, 2019; Gianni-Barrera et al, 2020)
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