A complex role for the progesterone receptor in the response to vascular injury
Richard H. Karas, … , Bert W. O’Malley, Michael E. Mendelsohn
Richard H. Karas, … , Bert W. O’Malley, Michael E. Mendelsohn
Published August 15, 2001
Citation Information: J Clin Invest. 2001;108(4):611-618. https://doi.org/10.1172/JCI11374.
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Article

A complex role for the progesterone receptor in the response to vascular injury

Abstract

Clinical studies of hormone replacement therapy to prevent cardiovascular diseases have heightened interest in the cardiovascular effects of progestins. However, the role of the progesterone receptor (PR) in vascular biology has not been studied in vivo. We studied ovariectomized female PR knockout (PRKO) mice and their wild-type (WT) littermates using the mouse carotid artery injury model. Placebo-treated PRKO mice showed significantly greater vascular medial hypertrophy and vascular smooth muscle cell (VSMC) proliferation in response to vascular injury than did WT mice. Progesterone had no significant effect in the PRKO mice, but worsened the response to injury in WT mice. VSMCs cultured from PRKO mouse aortae were markedly hyperproliferative, and their growth was not affected by progesterone. In contrast to the in vivo findings, progesterone inhibited proliferation of WT-derived VSMCs. Furthermore, reintroduction of PR into PRKO-derived VSMCs using adenoviral methods restored progesterone-mediated inhibition of proliferation to these cells. This effect was reversed by the PR antagonist, RU 486. Thus, the effects of PR and progesterone differ markedly between cultured VSMCs and intact blood vessels. These data demonstrate a direct role for the PR in regulating the response to vascular injury and VSMC proliferation.

Authors

Richard H. Karas, Martin van Eickels, John P. Lydon, Sean Roddy, Moon Kwoun, Mark Aronovitz, Wendy E. Baur, Orla Conneely, Bert W. O’Malley, Michael E. Mendelsohn

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Figure 6

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Progesterone-mediated inhibition of cultured VSMCs is mediated by the PR...
Progesterone-mediated inhibition of cultured VSMCs is mediated by the PR. (a) PRKO-derived VSMCs were infected with adeno-PRB at moi’s ranging from 1 to 50, and the effect of progesterone (Prog) on FBS-stimulated 3H-thymidine uptake was examined. Progesterone inhibited VSMC proliferation with the greatest effect at an moi of 50 for adeno-PRB. (Moi = 1, black bars; moi = 10, gray bars; and moi = 50, open bars; *P < 0.01 vs. moi 1, **P < 0.001 vs. moi 1, and P < 0.01 vs. moi 10). The inset depicts an immunoblot analysis demonstrating the expression of PRB in adeno-PRB–infected PRKO cells (moi = 50), while no expression was observed in adeno-GFP–infected PRKO VSMCs. The positive control (hBCa) was provided by the manufacturer. (b) After infection of PRKO-derived VSMCs with an moi of 50 for adeno-PRB, progesterone dose-dependently inhibited growth of these cells, and progesterone-mediated growth inhibition was abolished by coincubation with the PR antagonist RU 486 (*P < 0.01, **P < 0.001 vs. control cells treated with vehicle alone). In a and b, bars represent the mean ± SE of each of three independent experiments each performed with eight replicates per condition. For each cell type, the results are shown relative to the 3H-thymidine uptake in the vehicle-treated cells as the absolute rate of uptake was significantly higher in the PRKO-derived cells compared with the WT-derived cells (compare Figure 4).