Peripheral arterial disease (PAD) results from atherosclerosis and has two distinct clinical manifestations: intermittent claudication (IC, pain with walking relieved with rest), and critical limb ischemia (CLI, tissue loss). Even after adjusting for major demographic and clinical variables in PAD there is marked patient to patient clinical variability with comparable anatomic and hemodynamic findings. We identified the interleukin 21 receptor (IL21R) as a gene that modified the extent of angiogenesis, perfusion recovery and tissue loss following hind-limb ischemia (HLI) from inbred, and congenic, mouse strains. In endothelial cells (EC) in normoxic and growth factor rich settings IL21R had angiostatic effects but in PAD relevant conditions, hypoxia plus serum starvation (HSS), IL21R promoted angiogenesis (greater EC growth and tube formation, and less apoptosis) with STAT3 activation. Previously reported in-vivo, studies confirmed that IL21R up-regulation in hypoxic EC in ischemic muscle resulted in better perfusion recovery and less tissue loss and conversely the loss of the IL21R pathway poorer perfusion recovery and more tissue loss. In moving therapies from mouse to humans, numerous clinical trials in PAD have failed and the inability to fully appreciate the complexity of human PAD can indeed be a major reason. We will show that ischemic muscle from humans with CLI differs from IC in regards to IL21R expression in ischemic muscle and African Americans with CLI may have lower expression of this potentially beneficial receptor than Caucasians. We will show a) in-vivo and in-vitro that the IL21R system can promote hypoxia dependent angiogenesis without changes in VEGF protein, its receptor, or its Akt/eNOS/nitric oxide (NO) signaling pathway; b) in-vitro IL21R does not increase vascular permeability and cannot be blocked with NO inhibitors; and c) the IL21R pathway demonstrates efficacy in-vivo in HLI models where VEGF has failed. We have identified a micro-RNA (miR) that appears necessary for IL21R mediated hypoxia-dependent angiogenesis and can serve as a therapeutic where the IL21R cannot be targeted. A single long noncoding (lnc) RNA (IL21R-AS1) exists, is differentially expressed in PAD patients, and gain, and loss, of IL21R-AS1 had directionally opposite effects on angiogenesis in HUVEC under HSS. In paired central hypotheses, we posit that in humans therapeutic targeting of this unexpected angiogenic pathway will need to differ based on the PAD state and within individuals and IL21R mediated angiogenesis occurs via an eNOS independent pathway and miR-30b can serve as a therapeutic when the receptor is not available. The aims are: Aim 1): To assess human therapeutic targeting establish whether: a single strategy for all patients, distinct strategies by PAD clinical subgroups, or fully personalized strategies allows optimal targeting of IL21R mediated hypoxia-dependent angiogenesis. Aim 2): In-vitro and in-vivo contrast IL21R to VEGF in hypoxia dependent angiogenesis. Aim 3) Determine whether miR-30b is necessary for IL21R mediated hypoxic angiogenesis and can serve as a therapeutic alternative to IL21R in PAD conditions.