Genetic factors, which determine the degree of susceptibility to atherosclerosis may also influence the effects of estrogens and progestins in arterial vessel disease. We examined and compared estrogen receptor (ER) and progesterone receptor (PR) expression and the effects of 17-estradiol (E₂) and progesterone (P) on collagen synthesis and matrix metalloproteinase (MMP) activities in the aortic arch and in cultured aortic smooth muscle cells (ASMC) of atherosclerosis-susceptible (C57Bl6/J) or -resistant (C3H/HeJ) mice. ER, ER and PR levels were higher in the aorta and ASMC of atherosclerosis-susceptible C57Bl6/J mice. In transfection studies using an ERE-driven reporter plasmid, E₂ elicited an over 2-fold increase in luciferase activity in ASMC of C57Bl6/J (B6-ASMC), which demonstrated the transcriptional activity of ER in atherosclerosis-susceptible cells. Importantly, the response of endogenous target genes to E₂ and P was different in B6-ASMC and C3H-ASMC. E₂ decreased collagen synthesis but had no effect on MMP activities in B6-ASMC. P decreased MMP-2 and MMP-9 activity in B6-ASMC. In contrast, E₂ increased MMP-2 and decreased MMP-9 activity but had no effect on collagen synthesis in C3H-ASMC. P had no effect on collagen synthesis and MMP activity in C3H-ASMC. These differences in response to sex hormones may have important implications for women who receive hormone replacement therapy.