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For patients with chronic limb-threatening ischemia and limited revascularization options, alternate means for therapeutic angiogenesis and limb salvage are needed. E-selectin is a cell adhesion molecule that is critical for inflammation and neovascularization in areas of wound healing and ischemia. Here, we tested the efficacy of modifying ischemic limb tissue by intramuscular administration of E-selectin/AAV2/2 (adeno-associated virus serotype 2/2) to modulate angiogenic and inflammatory responses in a murine hindlimb gangrene model. Limb appearance, reperfusion, and functional recovery were assessed for 3 weeks after induction of ischemia. Mice receiving E-selectin/AAV2/2 gene therapy had reduced gangrene severity, increased limb and footpad perfusion, enhanced recruitment of endothelial progenitor cells, and improved performance on treadmill testing compared to control group. Histologically, E-selectin/AAV2/2 gene therapy was associated with increased vascularity and preserved myofiber integrity. E-selectin/AAV2/2 gene therapy also upregulated a panel of pro-angiogenic genes yet downregulated another group of genes associated with the inflammatory response. This novel gene therapy did not induce adverse effects on coagulability, or hematologic, hepatic, and renal function. Our findings highlight the potential of E-selectin/AAV2/2 gene therapy for improving limb perfusion and function in patients with chronic limb-threatening ischemia.

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Thromboangiitis obliterans, also known as Buerger’s disease, is a rare inflammatory vasculitis that predominantly develops in smokers and characteristically affects the small- and medium-sized peripheral arteries and veins. Patients typically present with extremity claudication, but symptoms may progress to rest pain and tissue loss, especially in those unable to abstain from tobacco use. Unfortunately, traditional medical treatments are largely ineffective and due to the small caliber of affected vessels and lack of suitable distal targets or venous conduits, endovascular and open surgical approaches are often not possible. Eventually, a significant number of patients require major amputation. For these reasons, much research effort has been made in developing techniques of therapeutic angiogenesis to improve limb perfusion, both for atherosclerotic peripheral arterial disease and the smaller subset of patients with critical limb ischemia due to Buerger’s disease. Neovascularization in response to ischemia relies on a complex interplay between the local tissue microenvironment and circulating stem and progenitor cells. To date, studies of therapeutic angiogenesis have therefore focused on exploiting known angiogenic factors and stem cells to induce neovascularization in ischemic tissues. This review summarizes the available clinical data regarding the safety and efficacy of various angiogenic therapies, notably injection of naked DNA plasmids, viral gene constructs, and cell-based preparations, and describes techniques for potentiating in vivo efficacy of gene- and cell-based therapies as well as ongoing developments in exosome-based cell-free approaches for therapeutic angiogenesis. Plain Language Title and Summary A review of available and emerging treatments for improving blood flow and wound healing in patients with Buerger’s disease, a rare disorder of blood vessels Buerger’s disease is a rare disorder of the small- and medium-sized blood vessels in the arms and legs that almost exclusively develops in young smokers. Buerger’s disease causes inflammation in arteries and veins, which leads to blockage of these vessels and reduces blood flow to and from the extremities. Decreased blood flow to the arms and legs can lead to development of nonhealing wounds and infection for which some patients may eventually require amputation. Unfortunately, traditional medical and surgical treatments are not effective in Buerger’s disease, so other methods for improving blood flow are needed for these patients. There are several different ways to stimulate new blood vessel formation, both in humans and animal models. The most common treatments involve injection of DNA or viruses that express genes related to blood vessel formation or, alternatively, stem cell–based treatments that help regenerate blood vessels and repair wound tissue. This review explores how safe and effective these various treatments are and describes recent research developments that may lead to better therapies for patients with Buerger’s disease and other vascular disorders.

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The response to ischemia in peripheral artery disease (PAD) depends on compensatory neovascularization and coordination of tissue regeneration. Identifying novel mechanisms regulating these processes is critical to the development of nonsurgical treatments for PAD. E-selectin is an adhesion molecule that mediates cell recruitment during neovascularization. Therapeutic priming of ischemic limb tissues with intramuscular E-selectin gene therapy promotes angiogenesis and reduces tissue loss in a murine hindlimb gangrene model. In this study, we evaluated the effects of E-selectin gene therapy on skeletal muscle recovery, specifically focusing on exercise performance and myofiber regeneration. C57BL/6J mice were treated with intramuscular E-selectin/adeno-associated virus serotype 2/2 gene therapy (E-sel/AAV) or LacZ/AAV2/2 (LacZ/AAV) as control and then subjected to femoral artery coagulation. Recovery of hindlimb perfusion was assessed by laser Doppler perfusion imaging and muscle function by treadmill exhaustion and grip strength testing. After three postoperative weeks, hindlimb muscle was harvested for immunofluorescence analysis. At all postoperative time points, mice treated with E-sel/AAV had improved hindlimb perfusion and exercise capacity. E-sel/AAV gene therapy also increased the coexpression of MyoD and Ki-67 in skeletal muscle progenitors and the proportion of Myh7+ myofibers. Altogether, our findings demonstrate that in addition to improving reperfusion, intramuscular E-sel/AAV gene therapy enhances the regeneration of ischemic skeletal muscle with a corresponding benefit on exercise performance. These results suggest a potential role for E-sel/AAV gene therapy as a nonsurgical adjunct in patients with life-limiting PAD.