Bone-marrow derived endothelial progenitor cells (EPCs) promote angiogenesis, and clinical trials suggest autologous EPC-based therapy may be effective in treatment of vascular diseases. Albeit promising, variability in the efficacy of EPCs associated with underlying disease states has hindered the realization of EPC-based therapy. Here we identify and characterize EPC dysfunction in a rodent model of vascular disease (SS/Mcwi rat) that exhibits impaired angiogenesis under physiological conditions, and develops cardiovascular disease on a high salt diet. First, we compared the angiogenic responses to EPCs delivered into the skeletal muscle of SS/Mcwi recipient prior to electrical stimulation. Delivery of EPCs from SS/Mcwi donors had no effect on angiogenesis compared to stimulation alone (9.2± 2.2% vs. 7.6 ± 1.7%, respectively). In contrast, introgression of chromosome 13 from a Brown Norway rat onto the SS/Mcwi background (SS-13BN/Mcwi rat) significantly enhanced the angiogenic function of EPCs (22.3 ± 3.7%) and suggests involvement of genes on chromosome 13. To identify molecular candidates that mediate the angiogenic potential of these cells, we performed a cell surface proteomic analysis. Analysis revealed that EPCs derived from SS/Mcwi rats express significantly more type 2 low-affinity immunoglobulin Fc-gamma (FCGR2, 25% increase) and Natural Killer 2B4 (CD244, 67% increase) receptors than EPCs from the SS-13BN/Mcwi rat. Genome-wide mRNA sequencing (RNAseq) revealed differential expression of multiple isoforms encoding FCGR2a and CD244 proteins, and qt-PCR confirmed an increase in CD244 and FCGR2a transcripts in SS/Mcwi EPCs. Increased expression of FCGR2a and CD244 receptors are predicted to increase the probability of SS/Mcwi EPCs being targeted for death, providing a mechanistic explanation for their reduced angiogenic efficacy in vivo. Pathway analysis supported this contention, as ‘key’ molecules annotated to cell death paths were differentially expressed in the SS/Mcwi EPC transcriptome. We speculate that screening and neutralization of cell surface proteins that tag ‘diseased’ EPCs for death will enhance regenerative potential of EPC-based therapies, providing a major advance in the field of regenerative medicine.