Occurrence and Functions of PACAP in the Placenta

Abstract

Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide with a widespread distribution both in the nervous system and peripheral organs. The peptide is also present in the female gonadal system, indicating its role in reproductive functions. While a lot of data are known on PACAP-induced effects in oogenesis and in the regulation of gonadotropin secretion at pituitary level, its placental effects are somewhat neglected in spite of the documented implantation deficit in mice lacking endogenous PACAP. The aim of the present review is to give a brief summary on the occurrence and actions of PACAP and its receptors in the placenta. Radioimmunoassay (RIA) measurements revealed increased serum PACAP levels during the third trimester and several changes in placental PACAP content in obstetrical pathological conditions, further supporting the function of PACAP during pregnancy. Both the peptide and its receptors have been shown in different parts of the placenta and the umbilical cord. PACAP influences blood vessel and smooth muscle contractility of the uteroplacental unit and is involved in regulation of local hormone secretion. The effects of PACAP on trophoblast cells have been mainly studied in vitro. Effects of PACAP on cell survival, angiogenesis and invasion/proliferation have been described in different trophoblast cell lines. PACAP increases proliferation and decreases invasion in proliferative extravillous trophoblast cells, but not in primary trophoblast cells, where PACAP decreased the secretion of various angiogenic markers. PACAP pretreatment enhances survival of non-tumorous primary trophoblast cells exposed to oxidative stress, but it does not influence the cell death-inducing effects of methotrexate in proliferative extravillous cytotrophoblast cells. Interestingly, PACAP has pro-apoptotic effect in choriocarcinoma cells suggesting that the effect of PACAP depends on the type of trophoblast cells. These data strongly support that PACAP plays a role in normal and pathological pregnancies and our review provides an overview of currently available experimental data worth to be further investigated to elucidate the exact role of this peptide in the placenta. Abstract Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide with a widespread distribution both in the nervous system and peripheral organs. The peptide is also present in the female gonadal system, indicating its role in reproductive functions. While a lot of data are known on PACAP-induced effects in oogenesis and in the regulation of gonadotropin secretion at pituitary level, its placental effects are somewhat neglected in spite of the documented implantation deficit in mice lacking endogenous PACAP. The aim of the present review is to give a brief summary on the occurrence and actions of PACAP and its receptors in the placenta. Radioimmunoassay (RIA) measurements revealed increased serum PACAP levels during the third trimester and several changes in placental PACAP conten...

Disturbed spermatogenic signaling in pituitary adenylate cyclase activating polypeptide-deficient mice

“…PACAPdeficient mice have been described to have impaired implantation (Isaac & Sherwood 2008), which, together with the increased rate of early postnatal death also leads to a reduced number of offspring (Gray et al 2001, Wilson & Cumming 2008. As PACAP is involved in several other processes, such as gametogenesis (Apa et al 2002, Li et al 2004, Barberi et al 2007, Koppan et al 2012, Canipari et al 2016, placental development (Horvath et al 2014(Horvath et al , 2016 and gonadotropin regulation (Kanasaki et al 2016), it can be hypothesized that lack of PACAP may also influence reproduction in germ cells (Lacombe et al 2006). In a previous study, we found that the diameter of sperm heads in PACAP-deficient mice was smaller, (Brubel et al 2012), but no data were obtained as to whether this resulted in abnormal motility.…”

Comparative analysis of decidual and peripheral immune cells and immune‐checkpoint molecules during pregnancy in wild‐type and PACAP‐deficient mice

“…Decreased mating behavior 9 and impaired implantation 10 as well as disturbed maternal behavior 9 and increased postnatal mortality with altered perinatal neurobehavioral development 11,12 in PACAP knockout mice have been suggested to account for the decreased number of offspring. For example, PACAP plays a role in fertilization, 13 influences trophoblast cell growth, migration, and placental functions 14 and plays a role in the blood flow of the uteroplacental unit. For example, PACAP plays a role in fertilization, 13 influences trophoblast cell growth, migration, and placental functions 14 and plays a role in the blood flow of the uteroplacental unit.…”

“…Several other effects of PACAP in reproductive functions have been suggested to play a role in the decreased reproductive rate described by several research groups. For example, PACAP plays a role in fertilization, 13 influences trophoblast cell growth, migration, and placental functions 14 and plays a role in the blood flow of the uteroplacental unit. 15 PACAP is a known modulator of innate and adaptive immune response.…”

Female reproductive functions of the neuropeptide PACAP

“…This was the case in choriocarcinoma cells, where PACAP treatment led to further decrease in survival in cells exposed to hydrogen peroxide-induced oxidative stress or chemically induced in vitro hypoxia ( 113 ). However, no effect was observed in lipopolysaccharide-, ethanol or methotrexate-treated cells ( 113 , 114 ). Furthermore, in JAR choriocarcinoma cells, PACAP influenced the expression of several signaling molecules, such as ERK1/2, JNK, Akt, GSK, Bax, p38 MAPK ( 113 ).…”