Ovulation: new factors that prepare the oocyte for fertilization

Abstract

Ovulation is a complex LH-induced process that allows the release of a fertilizable oocyte. Critical to ovulation is the proper formation of an extracellular hyaluronan (HA) rich matrix by the cumulus oocyte complex (COC), a process called expansion. During expansion genes associated matrix formation such as hyaluronan synthase 2 (HAS-2) are induced rapidly in COCs. To stabilize the long hyaluronan polymers, various HA binding proteins are covalently (or non-covalently) linked with hyaluronan. Some of the hyaluronan binding factors that have been identified in the COC matrix are the serum derived factor inter-alpha trypsin inhibitor (IalphaI) and tumor necrosis factor stimulated gene-6 (TSG-6). The latter is dependent on the induction in cumulus cells of cyclooxygenase-2 (COX-2) the limiting enzyme in the synthesis of prostaglandins (primarily PGE) that bind the PG receptor subtype EP2, leading to increased cAMP. TSG-6 and the heavy chains of I(alpha)I interact with each other and HA in a manner that is critical for the formation and/or stabilization of the expanded matrix. Another hyaluronan binding component of the expanded COC is the proteoglycan versican. Versican is induced by the LH surge and is a preferred substrate of the protease, a disintegrin and metalloproteinase with thrombospondin like repeats (ADAMTS-1), which co-localizes with versican and is coordinately induced in granulosa cells and COCs of ovulating follicles by LH and the progesterone receptor (PR). Mice null for COX-2 and EP2 fail to ovulate and exhibit impaired COC expression of TSG-6. Progesterone receptor knockout (PRKO) mice are also anovulatory and present impaired expression of ADAMTS-1. Thus, HA binding proteins and associated factors appear to be essential components of the matrix that is obligatory for release of the COCs through the ovulation pore.