Oxidatively modified low-density lipoprotein (oxLDL) plays a key role in the initiation of atherosclerosis by increasing monocyte adhesion. The mechanism that is responsible for the oxLDL-induced atherogenic monocyte recruitment in vivo, however, still remains unknown. Oxidation of LDL generates lysophosphatidylcholine, which is the main substrate for the lysophosphatidic acid (LPA) generating enzyme autotaxin. We show that oxLDL requires endothelial LPA receptors and autotaxin to elicit CXCL1-dependent arterial monocyte adhesion. Unsaturated LPA releases endothelial CXCL1, which is subsequently immobilized on the cell surface and mediates LPA-induced monocyte adhesion. Local and systemic application of LPA accelerates the progression of atherosclerosis in mice. Blocking the LPA receptors LPA(1) and LPA(3) reduced hyperlipidemia-induced arterial leukocyte arrest and atherosclerosis in the presence of functional CXCL1. Thus, atherogenic monocyte recruitment mediated by hyperlipidemia and modified LDL crucially depends on LPA, which triggers endothelial deposition of CXCL1, revealing LPA signaling as a target for cardiovascular disease treatments.

Objective-Hypoxia-inducible factor (HIF)-1␣ is the regulatory subunit of a transcriptional complex, which controls the recruitment of multipotent progenitor cells and tissue repair in ischemic tissue by inducing stromal cell-derived factor (SDF)-1␣ expression. Because HIF-1␣ can be activated under normoxic conditions in smooth muscle cells (SMCs) by platelet products, we investigated the role of HIF-1␣ in SDF-1␣-mediated neointima formation after vascular injury. Methods and Results-Wire-induced injury of the left carotid artery was performed in apolipoprotein E-deficient mice.HIF-1␣ expression was increased in the media as early as 1 day after injury, predominantly in SMCs. Nuclear translocation of HIF-1␣ and colocalization with SDF-1␣ was detected in neointimal cells after 2 weeks. HIF-1␣ mRNA expression was induced at 6 hours after injury as determined by real-time RT-PCR. Inhibition of HIF-1␣ expression by local application of HIF-1␣-siRNA reduced the neointimal area by 49% and significantly decreased the neointimal SMCs content compared with control-siRNA. HIF-1␣ and SDF-1␣ expression were clearly diminished in neointimal cells of HIF-1␣-siRNA treated arteries. Key Words: atherosclerosis Ⅲ restenosis Ⅲ vascular biology Ⅲ chemokines Ⅲ progenitor cells Ⅲ smooth muscle cells N eointima formation and inward remodeling are the basic mechanisms of the vascular response to mechanical injury, eg, by balloon angioplasty or stent implantation in obstructive coronary artery disease. 1,2 This can result in renarrowing of the target vessel, which is termed restenosis and limits therapeutic revascularization. 3 Initial endothelial denudation leads to an exposure of subendothelial matrix, which precipitates the adhesion of activated platelets and fibrin deposition, supporting the inflammatory recruitment of leukocytes. 4 The progress of neointimal hyperplasia is attributable to the accumulation of dedifferentiated smooth muscle cells (SMCs), which by far constitute the majority of neointimal cells. 5 The traditional idea of neointima formation focused on the concept that neointimal SMCs originate from medial cells within the vessel wall, which migrate into the intima and start to proliferate. 5,6 In recent years, evidence has accumulated that bone marrow-derived vascular progenitor cells participate significantly to neointima formation after selective recruitment to the injury site, thereby directing the vascular wound healing. 7 Smooth muscle progenitor cells (SPCs) have been detected in the peripheral blood of humans 8 and appear to be the critical vascular stem cell subtype for vascular repair after mechanical injury. Neointimal lesions after endothelial denudation consist of approximately 50% to 60% bone marrow-derived SMCs. 7 Among the multiple chemokines directing vascular cell trafficking, the CXC chemokine stromal cell-derived factor (SDF)-1␣ and its receptor CXCR4 represent an important molecular signaling axis for the mobilization and recruitment of SPCs. 9,10 In a "remote control" function, upregulation of SDF...