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

Clinical studies of hormone replacement therapy to prevent cardiovascular d iseases have heightened interest in the cardiovascular effects of progestin s. 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 ar tery injury model. Placebo-treated PRKO mice showed significantly greater v ascular medial hypertrophy and vascular smooth muscle cell (VSMC) prolifera tion in response to vascular injury than did WT mice. Progesterone had no s ignificant effect in the PRKO mice, but worsened the response to injury in WT mice. VSMCs cultured from PRKO mouse aortae were markedly hyperprolifera tive, 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 adenovira l methods restored progesterone-mediated inhibition of proliferation to the se cells. This effect was reversed by the PR antagonist, RU 486. Thus, the effects of PR and progesterone differ markedly between cultured VSMCs and i ntact blood vessels. These data demonstrate a direct role for the PR in reg ulating the response to vascular injury and VSMC proliferation.