Lipid-laden macrophages or "foam cells" are the primary components of the fatty streak, the earliest atherosclerotic lesion. Although Vav family guanine nucleotide exchange factors impact processes highly relevant to atherogenesis and are involved in pathways common to scavenger receptor CD36 signaling, their role in CD36-dependent macrophage foam cell formation remains unknown. The goal of the present study was to determine the contribution of Vav proteins to CD36-dependent foam cell formation and to identify the mechanisms by which Vavs participate in the process. We found that CD36 contributes to activation of Vav-1, -2, and -3 in aortae from hyperlipidemic mice and that oxidatively modified LDL (oxLDL) induces activation of macrophage Vav in vitro in a CD36 and Src family kinase-dependent manner. CD36-dependent uptake of oxLDL in vitro and foam cell formation in vitro and in vivo was significantly reduced in Vav null macrophages. These studies for the first time link CD36 and Vavs in a signaling pathway required for macrophage foam cell formation.Atherosclerosis is a complex inflammatory process driven in part by macrophage uptake of oxidized low density lipoproteins (oxLDL) 4 by scavenger receptors, such as CD36 and scavenger receptor A (1), leading to formation of lipid-laden "foam cells," the primary component of the earliest atherosclerotic lesions. Studies from our group and others demonstrated that CD36 accounts for a large proportion of foam cell formation in vitro and in vivo and that interruption of CD36 expression or downstream signaling blocks oxLDL uptake and limits experimental atherosclerosis in mice (2-9). CD36 is a multifunctional, multiligand transmembrane receptor expressed in a diverse array of cells including monocytes/macrophages, platelets, and adipocytes. Interestingly, CD36 deficiency is found in 0.5-1.0% of African and Asian populations (10, 11), and although atherosclerosis has yet to be studied in these groups, monocyte-derived macrophages collected from CD36-null individuals demonstrated 40% less binding and uptake of oxLDL compared with control individuals (12) with significant impairment of oxLDL-induced activation of NF-B and expression of proinflammatory genes (13). Numerous studies have revealed that CD36 acts as a signaling receptor, transmitting signals via Src family kinases (SFK) Lyn and Fyn, and MAP kinases JNK and p38, in response to multiple endogenous and exogenous ligands, including microbial pathogens, oxLDL, apoptotic cells, cell-derived microparticles, thrombospondin-related proteins, and amyloid peptides (14 -16). The precise molecular details, however, by which ligation of CD36 leads to recruitment and activation of a signaling complex are not fully understood. Identification of intracellular pathways required for oxLDL uptake and foam cell formation is vital for understanding the initiating stages of atherosclerosis and for designing novel targeted inhibitory agents. The studies outlined here demonstrate a critical role for Vav proteins in mediating CD36-depe...