Evidence for Autocrine or Paracrine Roles of α2-Macroglobulin in Regulation of Estradiol Production by Granulosa Cells and Development of Dominant Follicles

α2-Macroglobulin (α2-M) inhibits proteinases and modulates the actions of growth factors and cytokines. Despite the key roles proteinases, growth factors, and cytokines have in folliculogenesis, the role of α2-M in follicular development is unknown. Our objectives were to: 1) determine whether granulosa cells produce α2-M and have α2-M receptors, 2) examine the effect of α2-M on estradiol production by granulosa cells, 3) establish whether amounts of α2-M and α2-M receptors were altered during dominant nonovulatory follicle development, and 4) examine α2-M’s mechanism of action. The results demonstrated that bovine granulosa cells contain 5.2- and 15-kb mRNAs and 720- and 500-kDa proteins that correspond, respectively, to sizes of mRNAs and proteins for α2-M and the α2-M receptor. Treatment of granulosa cells with α2-M resulted in a specific dose-responsive increase in estradiol production. Cell viability, cell number, and the amount of aromatase in granulosa cells were not altered by α2-M. Treatment of granulosa cells with factors that bind α2-M or its receptor did not mimic α2-M action. Although intrafollicular amounts of α2-M remained unchanged, amounts of α2-M receptor in granulosa cells were strongly inversely associated with concentrations of estradiol in dominant and subordinate follicles. Based on these results, we concluded that α2-M may have autocrine or paracrine roles in granulosa cells potentially important for regulation of estradiol production and development of dominant follicles.