Systemic sclerosis (SSc) is an autoimmune, connective tissue disorder characterized by impaired vascular function, increased oxidative stress, inflammation of internal organs, and impaired angiogenesis. Tight skin mice (Tsk^-/+) have a defect in fibrillin-1, resulting in many of the myocardial and vascular features seen in SSc patients. D-4F is an apolipoprotein A-I mimetic that improves vascular function in diseases such as hypercholesterolemia, influenza, and sickle cell disease. Tsk^-/+ were treated with either phosphate buffered saline or D-4F. Acetylcholine and flow-induced vasodilation were examined in facialis arteries. Proinflammatory HDL (p-HDL) in murine and human plasma was determined by the cell-free assay. Angiostatin levels in murine and human plasma were determined by western blot. Hearts were examined for changes in angiostatin and autoantibodies against oxidized phosphotidyl choline (ox-PC). Angiogenic potential in sections of murine hearts was assessed by an in vitro VEGF-induced endothelial cell (EC) tube formation assay. D-4F improved endothelium-, eNOS-dependent and flow-mediated vasodilation in Tsk^-/+. Tsk^-/+ had higher plasma p-HDL and angiostatin levels than C57BL/6 mice as did SSc patients compared to healthy control subjects. D-4F reduced p-HDL and angiostatin in the plasma of Tsk^-/+. Tsk^-/+ hearts contained higher levels of angiostatin and autoantibodies against ox-PC than control hearts. D-4F ablated angiostatin in Tsk^-/+ hearts and reduced autoantibodies against ox-PC compared to hearts from untreated Tsk^-/+. Angiogenic potential in Tsk^-/+ hearts was increased when the Tsk^-/+ were treated with D-4F and cultured sections of hearts from the D-4F-treated Tsk^-/+were incubated with D-4F. Failure to treat the heart sections and Tsk^-/+ with D-4F resulted in loss of angiogenic potential. D-4F improves vascular function, decreases myocardial inflammation, and restores angiogenic potential in the hearts of Tsk^-/+. SSc patients have increased plasma p-HDL and angiostatin levels similar to the Tsk^-/+, D-4F may be effective at treating vascular complications in patients with SSc.