Expression of HIF-1α in Injured Arteries Controls SDF-1α–Mediated Neointima Formation in Apolipoprotein E–Deficient Mice

Abstract

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...

Effects of autologous SCF- and G-CSF-mobilized bone marrow stem cells on hypoxia-inducible factor-1 in rats with ischemia-reperfusion renal injury

“…In the treatment group, increased expression of HIF-1α was associated with quicker damage repair and increased metabolism. The enhanced expression of HIF-1α can improve the mobilization and recruitment effects of BMSCs by enhancing the activity of the SDF-1/CXCR4 axis (Karshovska et al, 2007), further accelerating tissue repair and enhancing local metabolism. This would increase local oxygen supply and demand and enhance the expression of HIF-1α.…”

Hyperreactivity of Junctional Adhesion Molecule A-Deficient Platelets Accelerates Atherosclerosis in Hyperlipidemic Mice

“…For immunoblotting or quantitative polymerase chain reaction, isolated platelets and harvested arteries after whole body perfusion with ice-cold phosphate-buffered saline solution (PBS; Sigma Aldrich) were homogenized and analyzed as described. 28 …”

Endothelial Hypoxia-Inducible Factor-1α Promotes Atherosclerosis and Monocyte Recruitment by Upregulating MicroRNA-19a

“…16,17 Vascular injury induces HIF-1α activation in smooth muscle cells and promotes neointima formation by upregulating CXCL12. 18 Here, we investigated the role of endothelial HIF-1α in atherosclerosis. We found that HIF-1α is activated in atherosclerotic ECs and deletion of endothelial HIF-1α reduces atherosclerosis, the lesional macrophage content, and the expression of CXCL1 and miR-19a in apolipoprotein E knockout (Apoe −/− ) mice.…”