Expression of metalloproteinases and their inhibitors in blood vessels in human endometrium

Matrix metalloproteinases (MMPs) are zinc-requiring enzymes that can degrad e components of the extracellular matrix and that are implicated in tissue remodeling. Their role in the onset of menstruation in vivo has been proven ; however, the expression and functions of MMPs and tissue inhibitors of me talloproteinases (TIMPs) in vascular structures are poorly understood. We d etermined by immunocytochemistry, using characterized monoclonal antibodies , the distribution of MMPs and of their inhibitors TIMP-1 and TIMP-2 in the endometrium during the menstrual cycle. MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1 , and TIMP-2 had differing distributions and patterns of expression. In add ition to the localization of MMP-9 in the epithelium and of MMP-2, MMP-3, a nd MMP-1 in the stromal tissue, these MMPs were detected in the vascular st ructures. MMP-2 (72-kDa gelatinase) and tissue inhibitors TIMP-1 and TIMP-2 were detectable in vessels throughout the cycle. In contrast, MMP-3 (strom elysin-l) was detected only in late-secretory and menstrual endometrial ves sels, while MMP-9 (92-kDa gelatinase) was detected in spiral arteries durin g the secretory phase and in vascular structures during the midfollicular a nd menstrual phases. The expression of MMP-2 and MMP-9 in endometrial vesse ls during the proliferative and secretory periods suggests their relationsh ip to vascular growth and angiogenesis. The pronounced expression of MMP-3 (stromelysin-l) in the vessels situated in the superficial endometrial laye r during menses suggests that this metalloproteinase initiates damage in th e vascular wall during menstrual breakdown. The finding of an intense expre ssion of TIMP-1 and TIMP-2 in the vessels delineating necrotic from non-nec rotic areas during menses also suggests that they could limit tissue damage , allowing regeneration of the endometrium after menses. These data indicat e that, in addition to expression in epithelial cells and stromal tissue, M MPs are expressed in endometrial vascular cells in a cycle-specific pattern , consistent with regulation by steroid hormones and with specific roles in the vascular remodeling processes occurring in the endometrium during the cycle.