Background and Purpose-Recent studies have shown that the cellular immune response in the development of vascular remodeling modulates the resulting pathological alterations. We show that hypoxia-inducible factor 1 (Hif-1) (specifically expressed in T cells) is involved in the immune response to vascular remodeling that accompanies arteriosclerosis. Methods and Results-To study the role of T cells in the development of vascular remodeling, femoral arterial injury induced by an external vascular polyethylene cuff was examined in mice lacking Hif-1 (specifically in T cells). We found that cuff placement caused prominent neointimal hyperplasia of the femoral artery in Hif-1-(T-cell)-deficient mice compared with that in control mice and that infiltration of inflammatory cells at the adventitia was markedly increased in the mutant mice. Studies to clarify the mechanism of augmented vascular remodeling in the mutant mice showed enhanced production of cytokines by activated T cells and augmented antibody production in response to a T-dependent antigen in the mutant mice. T he vascular response to mechanical arterial injury involved in arteriosclerosis or in-stent restenosis leads to neointimal formation and inward remodeling. Recent studies have shown that the immune system plays an important role in the development of vascular remodeling in response to arterial injury. 1 Studies 2-4 in mice have shown that arterial injury is associated with local accumulation of antibodies, and mice lacking functional T and B cells exhibit increased neointima formation, indicating that adaptive immune responses to neoantigens in the damaged tissue modulate the vascular remodeling. During the development of vascular remodeling, a hypoxic microenvironment accompanying arteriosclerosis or stent-mediated overdistention in the injured vascular region is thought to be one of the factors modulating proliferation of myofibroblasts and increased matrix synthesis in the adventitial region. 5 It has also been reported that hypoxia accelerates the progression of atherosclerosis 6,7 and modulates vascular remodeling after arterial injury. 8 Several studies 10,11 have shown evidence of hypoxia within the arterial wall in atherosclerosis in an animal model 9 and in human disease. Adaptation to low oxygen tension in local tissues is important for activities of immune cells, because immune cells are often exposed to different oxygen tensions that markedly affect cellular metabolism as they survey different tissue microenvironments. 12 Hypoxia-inducible factor 1 (Hif-1) is a transcription factor that regulates gene expression in response to hypoxia; it is composed of heterodimers of an oxygensensitive ␣ subunit and a constitutively expressed ␤ subunit (also known as arylhydrocarbon receptor nuclear translocator). Hif-1␣ regulates the expressions of genes in response to hypoxia to maintain physiological oxygen homeostasis. 14 In addition to hypoxic stabilization of Hif-1␣, resulting in upregulation of Hif-1␣ functions, several factors relevant to infla...

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) and excessive accumulation of dysfunctional PVAT are hallmarks of pathogenesis after angioplasty. Recent genome-wide association studies reveal that single-nucleotide polymorphism (SNP) in MIA3 is associated with atherosclerosis-relevant VSMC phenotypes. However, the role of MIA3 in the vascular remodeling response to injury remains unknown. Here, we found that expression of MIA3 is increased in proliferative VSMCs and knockdown of MIA3 reduces VSMCs proliferation, migration, and inflammation, whereas MIA3 overexpression promoted VSMC migration and proliferation. Moreover, knockdown of MIA3 ameliorates femoral artery wire injury-induced neointimal hyperplasia and increases brown-like perivascular adipocytes. Collectively, the data suggest that MIA3 deficiency prevents neointimal formation by decreasing VSMC proliferation, migration, and inflammation and maintaining BAT-like perivascular adipocytes in PVAT during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.