The development and demise of the corpus luteum (CL) are accompanied by angiogenic and angioregressive processes; however, the mediators of these processes have not been fully identified and characterized. Transcriptional profiling studies revealed the upregulation of cysteine-rich 61 (CYR61) in the CL, about which nothing was previously known. In the present study, we found that over a 12-h period following a single injection of prostaglandin F_2alpha (PGF_2alpha), RT-PCR revealed the upregulation of CYR61 at 0.5 and 1 h, after which it declined. We also determined that luteal-derived endothelial cells as well as luteal steroidogenic cells are sources of CYR61. Treatment with PGF_2alpha in vitro had no effect on CYR61 expression in luteal-derived endothelial cells, but it increased CYR61 expression in luteal steroidogenic cells. During the estrous cycle, CYR61/CYR61 (transcript/protein) was increased in the Day 4 but not in the Day 10 and Day 16 CL, suggesting that it may be associated with the switch to the angiogenic phenotype. In addition, the specific but transient upregulation of CYR61 by PGF_2alpha in vivo, and in luteal steroidogenic cells but not endothelial cells in vitro, may be part of the mechanism underlying the previously reported transient increase in blood flow during the early onset of luteolysis. This is supported by our preliminary finding that CYR61 transiently inhibited endothelial cell expression of endothelin-converting enzyme 1 mRNA but not endothelin 1. Collectively, the increased expression of CYR61 in the Day 4 CL and its transient increase by PGF_2alpha in Day 6, Day 10, and Day 16 CL indicate that CYR61 may play a role in regulating angiogenesis over the life span of the CL.