Role of Hypoxia-Inducible Factor 1α in T Cells as a Negative Regulator in Development of Vascular Remodeling

Abstract

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...

Pathophysiological Response to Hypoxia — From the Molecular Mechanisms of Malady to Drug Discovery: Inflammatory Responses of Hypoxia-Inducible Factor 1α (HIF-1α) in T Cells Observed in Development of Vascular Remodeling

“…This is supported by the results of our study showing enhanced IFN-γ production in activated T cells lacking expression of the Hif-1α gene (70). On the other hand, production of transcripts encoding IL-4 and IL-13, Th2-related cytokines, is also not impaired, suggesting possible roles for HIF-1 as a negative regulator in T cell activation.…”

“…Recent studies have also demonstrated that a hypoxic microenvironment during the development of arterial injury-induced vascular remodeling possibly affects the inflammatory progression and subsequent progressive pathological alterations (29, 46, 47, 62 -64). A vascular remodeling model, femoral arterial injury induced by an external vascular polyethylene cuff model (68,69), showed that hypoxia was present at the vascular wall around the cuff-injured artery and that HIF-1α-expressing T cells infiltrated around the hypoxic vascular region (70). These findings suggest that the function of infiltrating T cells around cuff-injured vessels in the development of vascular remodeling might be modulated by HIF-1α in a hypoxic microenvironment, even though there are many other modulators of HIF-1α besides hyp oxia in the vascular wall, such as inflammation and oxidative stress induced by factors such as nitric oxide, tumor necrosis factor (TNF)-α (17), angiotensin II (18), IL-1, insulin, and insulin-like growth factors (19,20).…”

“…These findings suggest that the function of infiltrating T cells around cuff-injured vessels in the development of vascular remodeling might be modulated by HIF-1α in a hypoxic microenvironment, even though there are many other modulators of HIF-1α besides hyp oxia in the vascular wall, such as inflammation and oxidative stress induced by factors such as nitric oxide, tumor necrosis factor (TNF)-α (17), angiotensin II (18), IL-1, insulin, and insulin-like growth factors (19,20). It has also been shown that hypoxia alone is not sufficient and that T cell receptor (TCR)-mediated signaling is required for accumulation of HIF-1α in peripheral T cells (70,71). TCR engagement does not influence hypoxia-dependent stabilization but stimulates synthesis of HIF-1α, probably via a PI3K/mammalian target of the rapamycin pathway (71).…”

“…A recent study demonstrated that cuff placement at the femoral artery caused prominent neointimal hyperplasia in Hif-1α-T cell-deficient mice compared to that in control mice (70). This finding of augmentation of arterial hyperplasia in the mutant mice and the results of several experiments on T cell-mediated immune responses in vivo and in vitro suggested that HIF-1α in T cells plays a crucial role in vascular inflammation and remodeling in response to cuff injury as a negative regulator of the T cell-mediated immune response, which includes regulating the production of cytokines and specific antibodies as described below.…”

“…Results of these studies have suggested that the adaptive immune system evoked by arterial tissue injury serves to limit the extent of the subsequent vascular repair process and that the mechanisms involved in restriction of the vascular repair process might include inhibition of smooth muscle cell growth by T cell-derived IFN-γ and antibody-mediated removal of proinflammatory debris. It has also been reported that aberrant production of IFN-γ and antibodies in mice lacking the Hif-1α gene in T cells might result in enhancement of arterial injury-mediated vascular remodeling, including neointima formation, suggesting that the immune response by HIF-1α in T cells is strictly regulated during vascular remodeling (70,72).…”