Abstract 147: Cell Selective Cardiovascular Biology of mPGES-1
Background— Global deletion of mPGES-1 attenuates the response to vascular injury without increasing predisposition to thrombogenesis or hypertension. However, enzyme deletion results in cell specific differential utilization of accumulated substrate. Here, we generated mice deficient in mPGES-1 in vascular smooth muscle cells (VSMC), endothelial cells (ECs) and myeloid cells to further elucidate the cell selective roles of this enzyme in cardiovascular biology.
Results— VSMC and EC mPGES-1 deficient mice were generated by mating mPGES-1flox/flox mice with SM22Cre or Tie2Cre mice respectively. Blood pressure was unaltered in these mutants at baseline or in response to a high salt diet. The propensity to induced thrombogenesis in a microvascular preparation was similarly unaltered. By contrast, both mPGES-1flox/floxSM22Cre and mPGES-1flox/floxTie2Cre mice exhibited a markedly exaggerated neointimal hyperplastic response to wire injury of the femoral artery compared to their mPGES-1flox/flox littermate controls (intima to media ratio 4.36 ± 0.63, 3.27 ± 0.23 versus 2.04 ± 0.31, p<0.01, n=8-13). The severity of neointimal hyperplasia was associated with increased proliferating cell nuclear antigen (PCNA) and tenascin-C (TN-C) expression. Macrophage mPGES-1 deficient mice (Mac-mPGES-1-KO) were generated by mating mPGES-1flox/flox mice with LysMCre mice. In these mice, the hyperplastic response to vascular injury was dramatically suppressed (intima to media ratio 2.59 ± 0.18 versus 1.47 ± 0.25, p<0.01, n=10) as was the expression of PCNA and TN-C. In vitro, conditioned medium derived from LPS-primed Mac-mPGES-1-KO macrophages was less potent than that from Mac-mPGES-1-WT macrophages in inducing VSMC proliferation and migration.
Conclusions— Deletion of mPGES-1 in vascular vs. myeloid cells results in contrasting vascular phenotypes. While enzyme knocked out in vascular cells does not augment thrombosis or predispose to hypertension, EC and VSMC mPGES-1 restrains the response to vascular injury. mPGES-1 in myeloid cells, by contrast, promotes the response to vascular injury and represents a potential therapeutic target.
- © 2012 by American Heart Association, Inc.