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Reversal of ischemia is mediated by neo-angiogenesis requiring endothelial cell (EC) and pericyte interactions to form stable microvascular networks. We describe an unrecognized role for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in potentiating neo-angiogenesis and vessel stabilization. We show that the endothelium is a major source of TRAIL in the healthy circulation compromised in peripheral artery disease (PAD). EC deletion of TRAIL in vivo or in vitro inhibited neo-angiogenesis, pericyte recruitment, and vessel stabilization, resulting in reduced lower-limb blood perfusion with ischemia. Activation of the TRAIL receptor (TRAIL-R) restored blood perfusion and stable blood vessel networks in mice. Proof-of-concept studies showed that Conatumumab, an agonistic TRAIL-R2 antibody, promoted vascular sprouts from explanted patient arteries. Single-cell RNA sequencing revealed heparin-binding EGF-like growth factor in mediating EC-pericyte communications dependent on TRAIL. These studies highlight unique TRAIL-dependent mechanisms mediating neo-angiogenesis and vessel stabilization and the potential of repurposing TRAIL-R2 agonists to stimulate stable and functional microvessel networks to treat ischemia in PAD. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD) is caused by blocked arteries due to atherosclerosis and/or thrombosis which reduce blood flow to the lower limbs. It results in major morbidity, including ischemic limb, claudication, and amputation, with patients also suffering a heightened risk of heart attack, stroke, and death. Recent studies suggest women have a higher prevalence of PAD than men, and with worse outcomes after intervention. In addition to a potential unconscious bias faced by women with PAD in the health system, with underdiagnosis, and lower rates of guideline-based therapy, fundamental biological differences between men and women may be important. In this review, we highlight sexual dimorphisms in endothelial cell functions and how they may impact PAD pathophysiology in women. Understanding sex-specific mechanisms in PAD is essential for the development of new therapies and personalized care for patients with PAD. [ABSTRACT FROM AUTHOR]

Current treatment of ischaemic vascular diseases such as coronary and peripheral artery disease includes angioplasty and bypass grafting, as well as lipid lowering therapies and control of other cardiovascular risk factors. Numerous members of the tumour necrosis factor superfamily (TNFSF) have recently shown emerging roles in both the protection and progression of such diseases. Understanding the role TNFSF members play in ischaemic vascular disease may provide insight into the development of novel therapeutics to prevent or treat diseases relating to atherosclerosis and ischaemia. This review summarizes the most recent findings relating to TNFSF members and the mechanisms that precede ischaemic vascular disease progression, particularly endothelial dysfunction, chronic inflammation, and atherosclerotic plaque development. This review also explores recent translational research on the role of TNFSF therapies in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Aims/Hypothesis: Peripheral arterial disease (PAD) is a major burden, resulting in limb claudication, repeated surgical interventions and amputation. There is an unmet need for improved medical management of PAD that improves quality of life, maintains activities of daily life and reduces complications. Nitric oxide (NO)/redox balance is a key regulator of angiogenesis. We have previously shown beneficial effects of a β 3 adrenergic receptor (β 3AR) agonist on NO/redox balance. We hypothesized that β 3AR stimulation would have therapeutic potential in PAD by promoting limb angiogenesis. Methods: The effect of the β 3AR agonist CL 316,243 (1–1,000 nmol/L in vitro , 1 mg/kg/day s. c) was tested in established angiogenesis assays with human endothelial cells and patient-derived endothelial colony forming cells. Post-ischemia reperfusion was determined in streptozotocin and/or high fat diet-induced diabetic and non-diabetic mice in vivo using the hind limb ischemia model. Results: CL 316,243 caused accelerated recovery from hind limb ischemia in non-diabetic and type 1 and 2 diabetic mice. Increased eNOS activity and decreased superoxide generation were detected in hind limb ischemia calf muscle from CL 316, 243 treated mice vs. controls. The protective effect of CL 316,243 in diabetic mice was associated with >50% decreases in eNOS glutathionylation and nitrotyrosine levels. The β 3AR agonist directly promoted angiogenesis in endothelial cells in vitro. These pro-angiogenic effects were β 3AR and NOS-dependent. Conclusion/Interpretation: β 3AR stimulation increased angiogenesis in diabetic ischemic limbs, with demonstrable improvements in NO/redox balance and angiogenesis elicited by a selective agonist. The orally available β 3AR agonist, Mirabegron, used for overactive bladder syndrome, makes translation to a clinical trial by repurposing of a β 3AR agonist to target PAD immediately feasible. [ABSTRACT FROM AUTHOR]