Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer’s disease.

Cyclooxygenases 1 and 2

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(14)61375-1.pdf

Cushing's syndrome

The Wharton's jelly of the umbilical cord contains mucoid connective tissue and fibroblast-like cells. Using flow cytometric analysis, we found that mesenchymal cells isolated from the umbilical cord express matrix receptors (CD44, CD105) and integrin markers (CD29, CD51) but not hematopoietic lineage markers (CD34, CD45). Interestingly, these cells also express significant amounts of mesenchymal stem cell markers (SH2, SH3). We therefore investigated the potential of these cells to differentiate into cardiomyocytes by treating them with 5-azacytidine or by culturing them in cardiomyocyte-conditioned medium and found that both sets of conditions resulted in the expression of cardiomyocyte markers, namely N-cadherin and cardiac troponin I. We also showed that these cells have multilineage potential and that, under suitable culture conditions, are able to differentiate into cells of the adipogenic and osteogenic lineages. These findings may have a significant impact on studies of early human cardiac differentiation, functional genomics, pharmacological testing, cell therapy, and tissue engineering by helping to eliminate worrying ethical and technical issues.

https://stemcellsjournals.onlinelibrary.wiley.com/doi/epdf/10.1634/stemcells.2004-0013

Mesenchymal Stem Cells in the Wharton's Jelly of the Human Umbilical Cord

Rheological and Physiological Consequences of Conversion of the Maternal Spiral Arteries for Uteroplacental Blood Flow during Human Pregnancy

We have examined factors concerned with the maintenance of uterine quiescence during pregnancy and the onset of uterine activity at term in an animal model, the sheep, and in primate species. We suggest that in both species the fetus exerts a critical role in the processes leading to birth, and that activation of the fetal hypothalamic-pituitary-adrenal axis is a central mechanism by which the fetal influence on gestation length is exerted. Increased cortisol output from the fetal adrenal gland is a common characteristic across animal species. In primates, there is, in addition, increased output of estrogen precursor from the adrenal in late gestation. The end result, however, in primates and in sheep is similar: an increase in estrogen production from the placenta and intrauterine tissues. We have revised the pathway by which endocrine events associated with parturition in the sheep come about and suggest that fetal cortisol directly affects placental PGHS expression. In human pregnancy we suggest that cortisol increases PGHS expression, activity, and PG output in human fetal membranes in a similar manner. Simultaneously, cortisol contributes to decreases in PG metabolism and to a feed-forward loop involving elevation of CRH production from intrauterine tissues. In human pregnancy, there is no systemic withdrawal of progesterone in late gestation. We have argued that high circulating progesterone concentrations are required to effect regionalization of uterine activity, with predominantly relaxation in the lower uterine segment, allowing contractions in the fundal region to precipitate delivery. This new information, arising from basic and clinical studies, should further the development of new methods of diagnosing the patient at risk of preterm labor, and the use of scientifically based strategies specifically for the management of this condition, which will improve the health of the newborn.

/pdf/endocrine-and-paracrine-regulation-of-birth-at-term-and-4igz1kdkru.pdf

Endocrine and paracrine regulation of birth at term and preterm

Angiogenesis and vascular remodeling are crucial processes in tumor invasion and metastasis as well as in embryo implantation and normal development of the placenta. We have previously shown that hCG expressed in trophoblast and various malignant tumors promotes cellular motility and that uterine endothelium expresses hCG/LH receptor in vivo. In this study hCG was proposed to promote angiogenesis. A three-dimensional in vitro angiogenesis system consisting of uterine microvascular endothelial cells seeded on microcarriers and entrapped in a fibrin matrix was used to study the influence of hCG on neovascularization. Physiological concentrations of hCG (5-50,000 mU/ml) significantly increased in vitro capillary formation (up to 2.5-fold) and migration of endothelial cells in a Boyden chamber assay (up to 3.6-fold) in a dose-dependent manner, whereas hCG had no effect on cell proliferation. In vivo, hCG induced neovascularization in the chicken chorioallantoic membrane assay comparable to the activity of vascular endothelial growth factor. hCG-secreting tumors (choriocarcinoma, endometrium, and ovarian carcinoma) promoted in vitro neovascularization (up to 3-fold), whereas hCG-neutralizing antibody, pertussis toxin (G protein inhibitor), or GRGDTP peptide (integrin antagonist), respectively, abolished both tumor- and hCG-induced capillary sprout formation. Our data indicate a novel function for hCG in uterine adaptation to early pregnancy as well as in tumor development and underline the importance of hCG as an as yet unrecognized angiogenic factor.

/pdf/characterization-of-human-chorionic-gonadotropin-as-a-novel-57cy1czxgs.pdf

Characterization of human chorionic gonadotropin as a novel angiogenic factor.

It has been well documented that a significant proportion of chronic anovulatory patients have elevated levels of dehydroepiandrosterone sulfate (DHEAS) and luteinizing hormone (LH) and normal levels of adrenocortiocotropic hormone (ACTH). We tested the hypothesis that the zones of human adrenal cortex that secrete DHEAS may contain LH/human chorionic gonadotropin (hCG) receptors. In situ hybridization showed the presence of hybridization signals representing LH/hCG receptor mRNA transcripts in the zona reticularis. Immunocytochemistry demonstrated that the zona reticularis also contained LH/hCG receptor protein. The receptor transcripts and receptor protein are also present in the deeper layer of the zona fasciculata which can also secrete DHEAS. Double immunostaining revealed that LH/hCG receptors are present in the same cells that contain cytochrome P450 side chain cleavage enzyme, suggesting that the receptor containing cells are steroidogenic. These findings may potentially explain higher DHEAS levels in chronic anovulatory women who have normal ACTH and elevated LH levels.

/pdf/novel-presence-of-luteinizing-hormone-chorionic-gonadotropin-1o2zpnu0yd.pdf

Novel presence of luteinizing hormone/chorionic gonadotropin receptors in human adrenal glands.

The present study investigated 1) whether extra- and intramyometrial arteries contain hCG/human LH receptor messenger ribonucleic acid (mRNA) and receptor protein, 2) whether hCG can bind to its vascular receptors and regulate the formation of vasoactive eicosanoids, and 3) whether hCG administration for ovulation induction can affect the vascular resistance in uterine arteries. The uterine arteries contain multiple hCG/LH receptor mRNA transcripts in endothelial and smooth muscle cells. The uterine arteries also contain an 80-kilodalton immunoreactive receptor protein in endothelial and smooth muscle cells. The extra- and intramyometrial arteries and an 80-kilodalton receptor protein bind [125I]hCG, which is inhibited by excess unlabeled hCG. The receptor mRNA, receptor protein, and ligand binding are higher in smaller intramyometrial arteries than in larger extramyometrial arteries. Incubation of uterine arteries with highly purified hCG resulted in a dose-dependent increase in immunoreactive cyclooxyge...

Expression of functional human chorionic gonadotropin/human luteinizing hormone receptor gene in human uterine arteries.

The human uterus, including its blood vessels, contains hCG/human LH receptors. We now demonstrate that human fallopian tubes also contain a 4.4-kilobase hCG/LH receptor mRNA transcript and an 80-kilodalton immunoreactive protein that can bind [125I]hCG. Tubal mucosa contain more receptor transcripts, receptor protein, and [125I] hCG binding than the tubal smooth muscle or blood vessels. Human fallopian tubes also contain hCG protein and a 0.6-kilobase hCG alpha mRNA transcript. However, very little hCG is found in tubal cell layers other than mucosa. Ampullary segments contain more hCG/LH receptors and hCG than isthmus. Secretory phase tubes contain more than proliferative phase, postpartum, or postmenopause tubes. Incubation with highly purified hCG resulted in an increase in catalytically active 5-lipoxygenase, cyclooxygenase-1, and cyclooxygenase-2 enzymes in tubal tissues. In summary, human fallopian tubes, which have never previously been considered a direct target of hCG/LH action, express function...

Novel coexpression of human chorionic gonadotropin (hCG)/human luteinizing hormone receptors and their ligand hCG in human fallopian tubes

Human endometrial stromal cells contain human CG (hCG)/LH receptors and in vitro, hCG/LH can promote stromal cells differentiation into decidua. In the present study, we tested the hypothesis that the treatment of stromal cells with exogenous hCG/LH to promote in up-regulation of cyclooxygenase-2 (COX-2) gene expression. The stromal cells from proliferative phase endometria were cultured for 10 days with 10 ng/ml estradiol and 100 ng/ml progesterone in the presence or absence of increasing concentrations of highly purified hCG. Northern blotting demonstrated that the cells contained a 4.4-kb COX-2 messenger RNA transcript whose levels significantly increased after treatment with hCG. Western blotting showed that the cells contained a 72-kDa COX-2 protein which also significantly increased after treatment with hCG. The effect of hCG on COX-2 messenger RNA and protein was seen at 10 ng/ml and higher concentrations sustained the increased levels. Although human LH mimicked hCG, human FSH, TSH, and isolated a...

/pdf/up-regulation-of-cyclooxygenase-2-gene-expression-by-1lmo4ulhlu.pdf

Up-regulation of cyclooxygenase-2 gene expression by chorionic gonadotropin during the differentiation of human endometrial stromal cells into decidua.

C V Rao

Papers

Characterization of human chorionic gonadotropin as a novel angiogenic factor.

Novel presence of luteinizing hormone/chorionic gonadotropin receptors in human adrenal glands.

Expression of functional human chorionic gonadotropin/human luteinizing hormone receptor gene in human uterine arteries.

Novel coexpression of human chorionic gonadotropin (hCG)/human luteinizing hormone receptors and their ligand hCG in human fallopian tubes

Up-regulation of cyclooxygenase-2 gene expression by chorionic gonadotropin during the differentiation of human endometrial stromal cells into decidua.