Ovarian acetylcholine and muscarinic receptors: Hints of a novel intrinsic ovarian regulatory system

Abstract

More than two decades ago, the degrading enzyme of the neurotransmitter acetylcholine (ACH) was reported in nerve fibers of the rat ovary. Subsequently, it was assumed that ACH is a neurotransmitter of ovarian nerves, although the sole presence of the degrading enzyme, ACH-esterase, does not allow such a conclusion. That ACH may be involved in the complex regulation of ovarian functions, including hormone production, was indicated by studies using, for example, granulosa cells (GCs). The lack of detailed information about both source(s) and functions of ACH in the ovary prompted us to examine sites of ovarian ACH-synthesis and ACH-receptor-bearing target cells. We also started to identify functions of ACH in cultured human GCs. While ovarian innervation and recently described neuron-like cells of the ovary were not immunoreactive for the ACH-synthesizing enzyme, choline-acetyl transferase (CHAT), we found immunoreactivity in GCs of rodents and primates. Isolated human and rat GCs produced ACH and contained the vesicular ACH transporter (VACHT). These results indicate that endocrine GCs are an unexpected non-neuronal source of ACH in the ovary. Moreover, these cells and GCs in vivo contain ACH-receptors of the muscarinic subtype (MR), namely M1R and M5R. In contrast, oocytes express M3R. MR of human GCs are functional and cholinergic stimulation is linked to rapid increases in intracellular Ca(++) levels. M1/5R activation also led to increased cell proliferation of human GCs in vitro and this stimulatory effect was found to be associated with rapid disruption of gap junction communication. Ongoing studies begin to identify regulation of ion channels and altered gene expression as consequences of MR stimulation. Thus, our results outline first details of an unexpected intraovarian, non-neuronal cholinergic system, and suggest that it may be involved in the regulation of cell proliferation in the ovary.

The cholinergic influence on the mesenteric ganglion affects the liberation of ovarian steroids and nitric oxide in oestrus day rats: characterization of an ex vivo system

“…It has been suggested that acetylcholine may play a role in the cellular proliferation (Gutkind et al 1991) and in the changes of the constantly remodelling ovarian tissue histoarchitecture (Lauder & Schambra 1999, Mayerhofer & Fritz 2002, both of which occur in this oestrous stage. It has also been described that cholinergic agents modify the secretion of hormones from human granulosa cells in culture (Bodis et al 1993).…”

“…Groups of six animals in oestrus (E) were used for the experimental procedure. This stage was chosen for three important reasons: first, because it is the period of the oestrous cycle when there is more ovarian irrigation, and the increased values of oestrogen cause a rapid dilation of blood vessels by activating endothelial NOS (Acosta & Miyamoto 2004); secondly, because the ONP fibres are mainly perivascular (Lawrence & Burden 1980) and could take part in the vascularization changes that occur in this stage; and thirdly, because it is a stage of deep biochemical and structural changes (Mayerhofer & Fritz 2002). The experiments were performed according to the procedures approved in the UFAW Handbook on the Care and Management of Laboratory Animals (Poole 1999) and the Guide for Animal Use and Handling of the National University of San Luis, Argentina.…”

Immunohistochemical and histochemical findings favoring the occurrence of autocrine/paracrine as well as nerve‐related cholinergic effects in chronic painful patellar tendon tendinosis

“…Mayerhofer and Fritz, 2002). This includes the situation for human keratinocytes, which are reported to synthesize, store, release and degrade ACh (Grando et al, 1993b).…”

“…On the basis of the findings of the present study it can be asked whether cholinergic influences take a part in these events. From this point of view it is of interest to note that cholinergic stimulation of the mAChRs (M 1 and M 5 ) of the human granulose cells leads to increased cell proliferation of these cells in vitro (Mayerhofer and Fritz, 2002). ACh has also been shown to markedly stimulate the proliferation of myofibroblastic hepatic stellate cells and to induce collagen gene expression in these cells (Oben et al, 2003).…”

The Cholinergic System Can Be of Unexpected Importance in Osteoarthritis

“…well-known effects on angiogenesis (Jacobi et al, 2002;Cooke et al, 2007). It is also known that an increased cell proliferation occurs in response to cholinergic stimulation (Mayerhofer & Fritz, 2002;Metzen et al, 2003;Oben et al, 2003). That includes proliferative effects on human fibroblasts .…”