An overlooked connection: serotonergic mediation of estrogen-related physiology and pathology

BACKGROUND: In humans, serotonin has typically been investigated as a neurotransmitter. However, serotonin also functions as a hormone across animal phyla, including those lacking an organized central nervous system. This hormonal action allows serotonin to have physiological consequences in systems outside the central nervous system. Fluctuations in estrogen levels over the lifespan and during ovarian cycles cause predictable changes in serotonin systems in female mammals. DISCUSSION: We hypothesize that some of the physiological effects attributed to estrogen may be a consequence of estrogen-related changes in serotonin efficacy and receptor distribution. Here, we integrate data from endocrinology, molecular biology, neuroscience, and epidemiology to propose that serotonin may mediate the effects of estrogen. In the central nervous system, estrogen influences pain transmission, headache, dizziness, nausea, and depression, all of which are known to be a consequence of serotonergic signaling. Outside of the central nervous system, estrogen produces changes in bone density, vascular function, and immune cell self-recognition and activation that are consistent with serotonin's effects. For breast cancer risk, our hypothesis predicts heretofore unexplained observations of the opposing effects of obesity pre- and post-menopause and the increase following treatment with hormone replacement therapy using medroxyprogesterone. SUMMARY: Serotonergic mediation of estrogen has important clinical implications and warrants further evaluation

Effect of medroxyprogesterone on depressive symptoms in depressed and nondepressed perimenopausal and postmenopausal women after discontinuation of transdermal estradiol therapy

Objective: Concern about adverse effects of progestins on mood has influenced the use of medroxyprogesterone (MPA) and other progestins. In this brief report, we examined whether the administration of MPA leads to depressive symptoms in two groups of perimenopausal and postmenopausal women randomly assigned to treatment with estrogen: one currently experiencing clinical depression and another without depression. Methods: Open-label MPA 10 mg/day was administered for 14 days for endometrial protection after completion of double-blinded treatment with 17β-estradiol 0.1 mg/day for 8 to 12 weeks in 40-to 60-year-old perimenopausal and postmenopausal women enrolled in two separate randomized placebo-controlled trials for treatment of cognitive problems ( nondepressed group ) or clinical depression ( depressed group ). Nonparametric tests were used to compare changes in depressive symptoms on the Beck Depression Inventory (BDI) within each group and between groups during MPA therapy. Results: Of the 24 nondepressed (median BDI at baseline, 5.5; interquartile range [IQR], 2.5-8.5) and 14 depressed (median BDI at baseline, 17; IQR, 15-21) women treated with MPA, the BDI scores did not change during MPA treatment in either group (median change, 0; IQR,-2 to 0.5 and median, 0; IQR,-0.5 to 1.5, P = 0.28 and P = 0.50, respectively). Changes in BDI scores during treatment with MPA did not differ between groups (P = 0.25). Conclusions: Among women receiving MPA for 2 weeks after discontinuation of estradiol, depressive symptoms did not emerge on MPA. These findings were consistent for both depressed and nondepressed women, suggesting that, even among women who are currently experiencing depression, brief treatment with MPA is unlikely to disrupt mood. © 2012 by The North American Menopause Society

Advantages of human umbilical vein scaffolds derived from cesarean section vs. vaginal delivery for vascular tissue engineering.

The current study investigated whether the mode of delivery and the mode of sample collection affect the functional properties of umbilical veins as scaffolds for vascular tissue engineering purposes. Human umbilical vein (HUV) from planned cesarean-sections (PCS) showed a 1.7-fold higher maximum contraction with potassium chloride compared to spontaneous vaginal deliveries (VDs, p=0.029). The maximum contractions with histamine were 2.0- and 2.9-fold higher in the PCS and emergency c-section (ECS) groups, respectively, compared to the VD group (p=0.003). The dose-response curves of serotonin were shifted to the right approx. 6- and 5-fold in the VD group compared to PCS and ECS, respectively (p=0.009). There were no differences between the birth groups in terms of tetrazolium dye reduction, platelet adhesion, and the structural integrity. The release of the antithrombotic compound prostacyclin from vessels of the PCS and ECS groups was 6.6- and 3.5-fold higher, respectively, than in the VD group (p<0.001). There was no correlation between the duration of ischemia and any of the functional parameters. This study provides evidence that vessels obtained from PCS are to be preferred for tissue engineering purposes, as they can be harvested in a sterile fashion and show superior vasoconstrictor responses and antithrombotic properties. The data also support a once-per-day pickup schedule for umbilical cords without a deterioration of the functional properties

Pharmacological characterization of prostanoid receptors mediating vasoconstriction in human umbilical vein

1. This study was undertaken to characterize pharmacologically the prostanoid receptor subtypes mediating contraction in human umbilical vein (HUV). 2. HUV rings were mounted in organ baths and concentration–response curves to U-46619 (TXA(2) mimetic) were constructed in the absence or presence of SQ-29548 or ICI-192,605 (TP receptor antagonists). U-46619 was a potent constrictor (pEC(50): 8.03). SQ-29548 and ICI-192,605 competitively antagonized responses to U-46619 with pK(B) values of 7.96 and 9.07, respectively. 3. Concentration–response curves to EP receptor agonists: PGE(2), misoprostol and 17-phenyl-trinor-PGE(2) gave pEC(50) values of 5.06, 5.25 and 5.32, respectively. Neither pEC(50) nor maximum of PGE(2) and 17-phenyl-trinor-PGE(2) concentration–response curves were modified by the DP/EP(1)/EP(2) receptor antagonist AH 6809 (1 μM). However, ICI-192,605 produced a concentration-dependent antagonism of the responses to all the EP receptor agonists. The pA(2) estimated for ICI-192,605 against PGE(2) or misoprostol were 8.91 and 9.22, respectively. 4. Concentration–response curves to FP receptor agonists: PGF(2)(α) and fluprostenol gave pEC(50) values of 6.20 and 5.82, respectively. ICI-192,605 (100 nM) was completely ineffective against PGF(2)(α) or fluprostenol. In addition, lack of antagonistic effect of AH 6809 (1 μM) against PGF(2)(α) was observed. 5. In conclusion, the findings obtained with TP-selective agonist and antagonists provide strong evidence of the involvement of TP receptors promoting vasoconstriction in HUV. Furthermore, the action of the natural and synthetic EP receptor agonists appears to be mediated via TP receptors. On the other hand, the results employing FP receptor agonists and antagonists of different prostanoid receptors suggest the presence of FP receptors mediating vasoconstriction in this vessel

Human Umbilical vein: Involvement of cyclooxygenase-2 pathway in bradykinin B1 receptor sensitized responses

In isolated human umbilical vein (HUV), the contractile response to des-Arg9-bradykinin (des-Arg9-BK), selective BK B1 receptor agonist, increases as a function of the incubation time. Here, we evaluated whether cyclooxygenase (COX) pathway is involved in BK B1-senzitized response obtained in 5-h incubated HUV rings. The effect of different concentrations of indomethacin, sodium salicylate, ibuprofen, meloxicam, lysine clonixinate or NS-398 administrated 30 min before concentration-response curves (CRC) was studied. All treatments produced a significant rightward shift of the CRC to des-Arg9-BK in a concentration-dependent manner, which provides pharmacological evidence that COX pathway is involved in the BK B1 responses. Moreover, in this tissue, the NS-398 pKb (5.2) observed suggests that COX-2 pathway is the most relevant. The strong correlation between published pIC50 for COX-2 and the NSAIDs' pKbs estimated further supports the hypothesis that COX-2 metabolites are involved in BK B1 receptor-mediated responses. In other rings, indomethacin (30, 100 μmol/l) or NS-398 (10, 30 μmol/l) produced a significant rightward shift of the CRC to BK, selective BK B2 agonist, and its pKbs were similar to the values to inhibit BK B1 receptor responses, suggesting that COX-2 pathway also is involved in BK B2 receptor responses. Western blot analysis shows that COX-1 and COX-2 isoenzymes are present before and after 5-h in vitro incubation and apparently COX-2 does not suffer additional induction.Fil: Errasti, Andrea Emilse. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rey Ares, Veronica. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Daray, Federico Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Rogines Velo, M. P.. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Sardi, Sergio Pablo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Farmacología; ArgentinaFil: Paz, Cristina del Valle. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Podesta, Ernesto Jorge. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; ArgentinaFil: Rothlin, Rodolfo Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas; Argentin

Pharmacological characterization of muscarinic receptor subtypes mediating vasoconstriction of human umbilical vein

1. The present study attempted to pharmacologically characterize the muscarinic receptor subtypes mediating contraction of human umbilical vein (HUV). 2. HUV rings were mounted in organ baths and concentration–response curves were constructed for acetylcholine (ACh) (pEC(50): 6.16±0.04; maximum response 80.00±1.98% of the responses induced by serotonin 10 μM). The absence of endothelium did not modify the contractile responses of ACh in this tissue. 3. The role of cholinesterases was evaluated: neither neostigmine (acetylcholinesterase inhibitor) nor iso-OMPA (butyrylcholinesterase inhibitor) modified ACh responses. When both enzymes were simultaneously inhibited, a significantly but little potentiation was observed (control: pEC(50) 6.33±0.03; double inhibition: pEC(50) 6.57±0.05). 4. Atropine, nonselective muscarinic receptors antagonist, inhibited ACh-induced contraction (pK(B) 9.67). The muscarinic receptors antagonists pirenzepine (M(1)), methoctramine (M(2)) and pFHHSiD (M(3)) also antagonized responses to ACh. The affinity values estimated for these antagonists against responses evoked by ACh were 7.58, 6.78 and 7.94, respectively. On the other hand, PD 102807 (M(4) selective muscarinic receptors antagonist) was ineffective against ACh-induced contraction. 5. In presence of a blocking concentration of pirenzepine, pFHHSiFD produced an additional antagonism activity on ACh-induced responses. 6. The M(1) muscarinic receptors agonist McN-A-343 produced similar maximum but less potent responses than ACh in HUV. The calculated pA(2) for pirenzepine against McN-A-343 induced responses was 8.54. 7. In conclusion, the data obtained in this study demonstrate the role of M(1) muscarinic receptor subtypes and suggest the involvement of M(3) muscarinic receptor subtypes in ACh-induced vasoconstriction in HUV rings. In addition, the vasomotor activity evoked by ACh does not seem to be modulated by endothelial factors, and their enzymatic degradation appears to have little functional relevance in this tissue