Abstract
Peripheral ischemia, resulting from diminished arterial flow and defective local vascularization, is one of the main causes of impaired wound healing in diabetes. Vasodilatory prostaglandins (PGs), including PGE2 and PGI2, regulate blood flow in peripheral tissues. PGs also stimulate angiogenesis by inducing vascular endothelial growth factor. However, PG levels are reduced in diabetes mainly due to enhanced degradation. We hypothesized that inhibition of the prostaglandin transporter (PGT) (SLCO2A1), which mediates the degradation of PGs, would increase blood flow and stimulate vascularization, thereby mitigating peripheral ischemia and accelerating wound healing in diabetes. Here we report that inhibiting PGT with intravenously injected PGT inhibitor, T26A, increased blood flow in ischemic hind limbs created in non-diabetic rats and streptozotocin induced diabetic rats. Systemic, or combined with topical, T26A accelerated closure of cutaneous wounds. Immunohistochemical examination revealed that inhibition of PGT enhanced vascularization (marked by larger numbers of vessels formed by CD34+ cells), and accelerated re-epithelialization of cutaneous wounds. In cultured primary human bone marrow CD34+ cells and human epidermal keratinocytes (HEKs) either inhibiting or silencing PGT increased migration in both cell lines. Thus PGT directly regulates mobilization of endothelial progenitor cells (EPCs) and HEKs, which could contribute to PGT-mediated vascularization and re-epithelialization. At the molecular level, systemic inhibition of PGT raised circulating PGE2. Taken together, our data demonstrate that PGT modulates arterial blood flow, mobilization of EPCs and HEKs, and vascularization and epithelialization in wound healing by regulating vasodilatory and pro-angiogenic PGs.
Highlights
Diabetes-associated non-healing lower extremity wounds, including leg ulcers and foot ulcers, are major contributors to non-combat limb loss [1]
Peripheral ischemia has a direct adverse impact on wound healing [34]. It is strongly associated with diabetes [30] and 46% of amputations in diabetic patients can be attributed to ischemia [35]
By using diabetic rats and their non-diabetic matched controls, we identified a novel modulator of perfusion, prostaglandin transporter (PGT), and tested inhibition of PGT as an innovative strategy to mitigate peripheral ischemia and correct defective wound healing in diabetes
Summary
Diabetes-associated non-healing lower extremity wounds, including leg ulcers and foot ulcers, are major contributors to non-combat limb loss [1]. Impaired wound healing in diabetes is multi-factorial, including peripheral ischemia due to diminished arterial blood flow and defective local vascularization[2,3]. Blood flow from arteries mobilizes nutrients, progenitor cells, and other molecular mediators to peripheral tissues during wound healing, and is a prerequisite for mounting a successful repair response [4]. Endothelial progenitor cells (EPCs), mobilized by blood flow, support vascularization, which are essential for wound healing. Occlusive peripheral arteries limit blood flow to distal tissues [5,6,7,8]. The endothelium is dysfunctional and EPCs are reduced [9,10], such that, at diabetic wound sites, these cells are incapable of properly forming vessels in a timely manner [11]
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