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Effect Of Estrogen And Progesterone On Matrix Metalloproteinase Gene Expression And Function In Human Aortic Vascular Smooth Muscle Cells

Oscar H Grandas, Stacy S Kirkpatrick, Deidra J H Mountain, Eva F Bukovska, Wendy K Packan, Allison D Stewart, David C Cassada, Scott L Stevens, Michael B Freeman, Mitchell H Goldman.
University of Tennessee Medical Center at Knoxville, Knoxville, TN.

OBJECTIVES: Postmenopausal females receiving hormone replacement therapy have worse outcomes after vascular reconstructions. Matrix metalloproteinase (MMP) pathway is regulated by a balance between MMPs, MT1-MMP and tissue inhibitor of MMPs (TIMPs). We hypothesize that estrogen and progesterone (E2/P) upregulate MMP/TIMP pathway through the mediation of MT1-MMP in human aortic vascular smooth muscle cells (VSMC).

METHODS: VSMC were incubated with IL-1B, E2 (5 ng/mL), P (50 ng/mL) and doxycycline. MMP-2, -9, TIMP-2, and MT1-MMP mRNA levels were determined by RT-PCR. Western Blot analysis was used to detect MMP and TIMP protein levels. In-gel zymography analysis measured MMP activity. VSMC invasion was measured by cell migration assay.

RESULTS: MT1-MMP and TIMP-2 mRNA levels were increased by E2 + IL-1B treatment as compared to control (47±23%, P<0.05 and 21±2%, respectively). Combined treatment with E2+IL-1B and doxycycline resulted in a significant synergistic increase of TIMP-2 mRNA (58%, P<0.05). E2/P + IL-1B increased MMP-2 (13±3%, n=2) protein levels. E2/P + IL-1B increased MMP-2 and -9 activity (19±9% and 9±2%, respectively, n=2). Doxycycline inhibited basal and E2/P+IL-1B stimulated MMP-2 activity (- 59±8% vs. control, n=2). VSMC invasion was enhanced by E2/P and blocked by doxycycline.

CONCLUSIONS: E2/P affects the MMP pathway by increasing MT1-MMP mRNA more than TIMP mRNA, resulting in increased MMP2/9 protein level and activity. In our study the E2/P effect on MMP2/9 activity is responsible for the enhanced VSMC invasion. E2/P upregulation of MT1-MMP may explain the adverse effect of hormone replacement therapy on vascular interventions.