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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Design of the carotid artery injury study. All animals were ovariectomiz...
Design of the carotid artery injury study. All animals were ovariectomized (OVX) and then allowed to recover for 7–10 days. Progesterone-containing or placebo pellets were then implanted subcutaneously 1 week before the animals underwent unilateral carotid injury and implantation of an osmotic mini-pump containing BrdU. On day 14 after injury, the animals were sacrificed and both carotid arteries were perfusion fixed, harvested, and then embedded in paraffin. Subsequently, the vessels were sectioned transversely and stained to allow morphometric and immunohistochemical analysis of the response to injury. Further details of the procedure have been published previously (35–37).