Role of hypoxia-inducible factor 1alpha in T cells as a negative regulator in development of vascular remodeling.

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. CONCLUSIONS: The results of this study revealed that Hif-1alpha in T cells plays a crucial role in vascular inflammation and remodeling in response to cuff injury as a negative regulator of T cell-mediated immune response. Potential new therapeutic strategies that target Hif-1alpha are described.

Syngeneic bone marrow mononuclear cells improve pulmonary arterial hypertension through vascular endothelial growth factor upregulation.

BACKGROUND: We investigated the effects and possible mechanism of syngeneic bone marrow mononuclear cell (BM-MNC) transplantation on pulmonary arterial hypertension induced by monocrotaline. METHODS: Monocrotaline (80 mg/kg body weight) was administrated to C57BL/6 mice, and pulmonary arterial hypertension was induced 4 weeks later. Bone marrow mononuclear cells harvested from syngeneic donor mice were injected intravenously into those mice 4 weeks after monocrotaline administration. The ratio of right ventricular to septum plus left ventricular weight, the number of small pulmonary arteries, and medial thickness of pulmonary arteries were measured. Western immunoblotting of the lung tissue was performed to observe vascular endothelial growth factor and its receptor expression 1 week after BM-MNC transplantation. Vascular endothelial growth factor receptor-2 inhibitor was administered to pulmonary arterial hypertension mice simultaneously with BM-MNC transplantation. RESULTS: The ratio of right ventricular to septum plus left ventricular weight increased, the number of pulmonary arteries decreased, and medial thickness increased significantly 4 weeks after monocrotaline injection compared with those of vehicle-injected mice. These indices of monocrotaline-injected mice improved significantly 4 weeks after BM-MNC transplantation compared with those of mice at 8 weeks after monocrotaline injection (0.22 +/- 0.02 versus 0.31 +/- 0.02; 17.1 +/- 2.6 versus 8.2 +/- 1.7; 7.7% +/- 2.2% versus 20% +/- 2.1%, respectively; p < 0.01). However, BM-MNCs were not incorporated into the lung at 1 week after transplantation, and significant vascular endothelial growth factor upregulation and without receptor expression was observed in lung tissue 1 week after transplantation. Improvement of pulmonary arterial hypertension was inhibited by simultaneous administration of vascular endothelial growth factor receptor-2 inhibitor with BM-MNC transplantation. CONCLUSIONS: These results indicate that syngeneic BM-MNC transplantation improves monocrotaline-induced pulmonary arterial hypertension by favorable pulmonary artery remodeling through vascular endothelial growth factor upregulation.

Left axillary artery perfusion in surgery of type A aortic dissection.

PURPOSE: A left axillary artery perfusion instead of a femoral perfusion has the benefit of avoiding false lumen perfusion and atheroembolization into the brain, which is caused by retrograde perfusion in type A aortic dissection surgery. We performed type A aortic dissection surgery using the left axillary artery perfusion technique and reviewed this method. PATIENTS AND METHODS: From April 2002 to January 2004, 8 patients with a mean age of 70 years (48 to 81), underwent axillary artery cannulation with a side graft technique in type A aortic dissection operations. Six patients had acute type A and 2 had chronic type A dissections. The surgical procedures were ascending aortic replacement in 5, hemiarch replacement in 2, and total arch replacement in 1. RESULTS: In all patients, a cardiopulmonary bypass was established through the left axillary perfusion. There were no operative deaths and no hospital deaths. All patients were able to avoid cerebral vascular accidents. One patient required a femoro-femoro bypass on the 10th postoperative day because of malperfusion of the left leg, which occurred suddenly. Postoperative hemorrhaging requiring resternotomy occurred in 2 patients. CONCLUSION: A left axillary artery perfusion is safe and useful for arterial inflow for type A aortic dissection surgery.