Coronary artery disease caused by atherosclerosis is a major cause of morbidity and mortality around the world. Data from preclinical and clinical studies support the belief that atherosclerosis is an inflammatory disease that is mediated by innate and adaptive immune signaling mechanisms. This review sought to highlight the role of Rac-mediated inflammatory signaling in the mechanisms driving atherosclerotic calcification. In addition, current clinical treatment strategies that are related to targeting hypercholesterolemia as a critical risk factor for atherosclerotic vascular disease are addressed in relation to the effects on Rac immune signaling and the implications for the future of targeting immune responses in the treatment of calcific atherosclerosis.

Aging and age-related diseases like peripheral arterial disease are associated with impaired inflammatoryarteriogenesis in response to injury. During ischemia, macrophage recruitment and macrophage pro-angiogenic VEGF-A isoform expression contribute to post developmental arteriogenesis. Preliminary datafrom bone marrow-derived macrophages (BMDMs) demonstrated decreased VEGF-A level by both mRNAand protein in aged (52-week-old) and advanced aged (104-week-old) mice when compared to young (12-week-old). Moreover, VEGF-A165a which is VEGF-A proangiogenic splice variant was also reduced inmacrophages from aged and advanced aged mice. The anti-angiogenic VEGF-A165b variant wassignificantly increased in advanced aged mice. We sought to determine the mechanisms which cancontribute to the reduction of pro-angiogenic VEGF-A and consequently reduced inflammatory-mediatedarteriogenesis response in the context of aging. In a hindlimb ischemia model of angio/arteriogenesis, wefound decreased blood flow recovery in aged mice. Moreover, small arterial angiography by microCTconfirmed decreased arteriogenesis. Loss of functional arteriogenesis was associated with decreased muscletissue VEGF-A and VEGF-A165a levels despite adequate macrophage recruitment to the muscle tissue.Moreover, VEGF-A165b was increased in ischemic tissue from advanced aged mice. The mechanism ofreduced macrophage pro-angiogenic VEGF-A165a expression involved decreased mRNA stability withdecreased association of VEGF-A165a mRNA with the RNA-stabilizing protein HuR. In fact, aged BMDMsdemonstrated a loss of HuR binding to VEGF-A165a mRNA with decreased VEGF-A165a mRNA half-life,and consequently decreased inflammatory angio/arteriogenesis.