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Vascular remodeling in a mouse model of obesity
Author(s) -
Rudic R. Daniel,
Stepp David W.,
Simkins G. Bryan,
Marrero Mario B.,
Fulton David
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a231-a
Subject(s) - medicine , endocrinology , leptin , leptin receptor , genetically modified mouse , neointimal hyperplasia , vascular remodelling in the embryo , endothelium , receptor , obesity , transgene , restenosis , biology , biochemistry , stent , gene
Mutation of the leptin receptor in mice (db/db) causes striking obesity and insulin resistance which may negatively impact the vasculature. Surprisingly, previous studies have suggested that these obese mice are protected from vascular injury. However, denudation of the endothelium used to provoke injury in these studies may mask a protective role for leptin within the vascular endothelium. To address this possibility, we implemented a non‐denuding model of flow‐induced vascular remodeling. Endothelial integrity in remodeled arteries was preserved as assessed by PECAM immunohistochemistry in both control (lean) mice and db/db (obese) mice. Arteries of lean mice exhibited typical inward vascular remodeling as expected, but remodeled vessels of obese mice exhibited robust intimal hyperplasia in response to the remodeling stimulus. To assess the impact of glycemia on the vascular remodeling response, we generated mice that were obese but normoglycemic (obese‐NG). This was accomplished by intercrossing the obese mice that were deficient in the leptin receptor to mice deficient in PTP1B, an insulin receptor phosphatase, which when disrupted in mice, causes insulin hypersensitivity. Though blood glucose levels were elevated in obese mice, blood glucose was restored to normal in the doubly transgenic obese‐NG mice, as revealed by levels of glycosylated hemoglobin (obese, 9.48%±0.44; obese‐NG, 6.84%±0.44; lean, 4.98%±0.14). Furthermore, remodeled arteries from the obese‐NG mice were protected from the neointimal formation that occurred in the obese mice. These data suggest that the leptin pathway restrains PTP1B signaling to improve glycemia and retard pathological remodeling.