Browsing by Author "Corthorn H., Jenny"

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    Administration of angiotensin II and a bradykinin B2 receptor blocker in midpregnancy impairs gestational outcome in guinea pigs
    (2014) Valdés Stromilli, Gloria; Schneider, Daniela; Corthorn H., Jenny; Ortíz, Rita; Acuña, Stephanie; Padilla, Oslando
    Abstract Background The opposing renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) are upregulated in pregnancy and localize in the utero-placental unit. To test their participation as counter-regulators, circulating angiotensin II (AII) was exogenously elevated and the bradykinin B2 receptor (B2R) was antagonized in pregnant guinea-pigs. We hypothesized that disrupting the RAS/KKS balance during the period of maximal trophoblast invasion and placental development would provoke increased blood pressure, defective trophoblast invasion and a preeclampsia-like syndrome. Methods Pregnant guinea-pigs received subcutaneous infusions of AII (200 μg/kg/day), the B2R antagonist Bradyzide (BDZ; 62.5 microg/kg/day), or both (AII + BDZ) from gestational day 20 to 34. Non-pregnant cycling animals were included in a control group (C NP) or received AII + BDZ (AII + BDZ NP) during 14 days. Systolic blood pressure was determined during cycle in C NP, and on the last day of infusion, and 6 and 26 days thereafter in the remaining groups. Twenty six days after the infusions blood and urine were extracted, fetuses, placentas and kidneys were weighed, and trophoblast invasion of spiral arteries was defined in the utero-placental units by immunocytochemistry. Results Systolic blood pressure transiently rose in a subgroup of the pregnant females while receiving AII + BDZ infusion, but not in AII + BDZ NP. Plasma creatinine was higher in AII- and BDZ-treated dams, but no proteinuria or hyperuricemia were observed. Kidney weight increased in AII + BDZ-treated pregnant and non-pregnant females. Aborted and dead fetuses were increased in dams that received AII and AII + BDZ. The fetal/placental weight ratio was reduced in litters of AII + BDZ-treated mothers. All groups that received interventions during pregnancy showed reduced replacement of endothelial cells by extravillous trophoblasts in lateral and myometrial spiral arteries. Conclusions The acute effects on fetal viability, and the persistently impaired renal/placental sufficiency and incomplete arterial remodeling implicate the RAS and KKS in the adaptations in pregnancy. The results partially confirm our hypothesis, as a preeclampsia-like syndrome was not induced. We demonstrate the feasibility of characterizing systemic and local modifications in pregnant guinea-pig, supporting its use to study normal placentation and related disorders.Abstract Background The opposing renin-angiotensin system (RAS) and kallikrein-kinin system (KKS) are upregulated in pregnancy and localize in the utero-placental unit. To test their participation as counter-regulators, circulating angiotensin II (AII) was exogenously elevated and the bradykinin B2 receptor (B2R) was antagonized in pregnant guinea-pigs. We hypothesized that disrupting the RAS/KKS balance during the period of maximal trophoblast invasion and placental development would provoke increased blood pressure, defective trophoblast invasion and a preeclampsia-like syndrome. Methods Pregnant guinea-pigs received subcutaneous infusions of AII (200 μg/kg/day), the B2R antagonist Bradyzide (BDZ; 62.5 microg/kg/day), or both (AII + BDZ) from gestational day 20 to 34. Non-pregnant cycling animals were included in a control group (C NP) or received AII + BDZ (AII + BDZ NP) during 14 days. Systolic blood pressure was determined during cycle in C NP, and on the last day of infusion, and 6 and 26 days thereafter in the remaining groups. Twenty six days after the infusions blood and urine were extracted, fetuses, placentas and kidneys were weighed, and trophoblast invasion of spiral arteries was defined in the utero-placental units by immunocytochemistry. Results Systolic blood pressure transiently rose in a subgroup of the pregnant females while receiving AII + BDZ infusion, but not in AII + BDZ NP. Plasma creatinine was higher in AII- and BDZ-treated dams, but no proteinuria or hyperuricemia were observed. Kidney weight increased in AII + BDZ-treated pregnant and non-pregnant females. Aborted and dead fetuses were increased in dams that received AII and AII + BDZ. The fetal/placental weight ratio was reduced in litters of AII + BDZ-treated mothers. All groups that received interventions during pregnancy showed reduced replacement of endothelial cells by extravillous trophoblasts in lateral and myometrial spiral arteries. Conclusions The acute effects on fetal viability, and the persistently impaired renal/placental sufficiency and incomplete arterial remodeling implicate the RAS and KKS in the adaptations in pregnancy. The results partially confirm our hypothesis, as a preeclampsia-like syndrome was not induced. We demonstrate the feasibility of characterizing systemic and local modifications in pregnant guinea-pig, supporting its use to study normal placentation and related disorders.
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    Angiogenic, hyperpermeability and vasodilator network in utero-placental units along pregnancy in the guinea-pig (Cavia porcellus)
    (2008) Valdés Quezada, Gloria.; Erices, Rafaela.; Chacón, Cecilia; Corthorn H., Jenny
    Abstract Background The angiogenic and invasive properties of the cytotrophoblast are crucial to provide an adequate area for feto-maternal exchange. The present study aimed at identifying the localization of interrelated angiogenic, hyperpermeability and vasodilator factors in the feto-maternal interface in pregnant guinea-pigs. Methods Utero-placental units were collected from early to term pregnancy. VEGF, Flt-1, KDR, B2R and eNOS were analyzed by immunohistochemistry, and the intensity of the signals in placenta and syncytial streamers was digitally analysed. Flt1 and eNOS content of placental homogenates was determined by western blotting. Statistical analysis used one-way analysis of variance and Tukey's Multiple Comparison post-hoc test. Results In the subplacenta, placental interlobium and labyrinth VEGF, Flt-1, KDR, B2R and eNOS were expressed in all stages of pregnancy. Syncytial streamers in all stages of gestation, and cytotrophoblasts surrounding myometrial arteries in early and mid pregnancy – and replacing the smooth muscle at term – displayed immunoreactivity for VEGF, Flt-1, KDR, eNOS and B2R. In partly disrupted mesometrial arteries in late pregnancy cytotrophoblasts and endothelial cells expressed VEGF, Flt-1, KDR, B2R and eNOS. Sections incubated in absence of the first antibody, or in presence of rabbit IgG fraction and mouse IgG serum, yielded no staining. According to the digital analysis, Flt-1 increased in the placental interlobium in days 40 and 60 as compared to day 20 (P = 0.016), and in the labyrinth in day 60 as compared to days 20 and 40 (P = 0.026), while the signals for VEGF, KDR, B2R, and eNOS showed no variations along pregnancy. In syncytial streamers the intensity of VEGF immunoreactivity was increased in day 40 in comparison to day 20 (P = 0.027), while that of B2R decreased in days 40 and 60 as compared to day 20 (P = 0.011); VEGF, Flt-1, KDR, B2R and eNOS expression showed no variations. Western blots for eNOS and Flt-1 in placental homogenates showed no significant temporal differences along pregnancy. Conclusion The demonstration of different angiogenic, hyperpermeability and vasodilator factors in the same cellular protagonists of angiogenesis and invasion in the pregnant guinea-pig, supports the presence of a functional network, and strengthens the argument that this species provides an adequate model to understand human pregnancy.Abstract Background The angiogenic and invasive properties of the cytotrophoblast are crucial to provide an adequate area for feto-maternal exchange. The present study aimed at identifying the localization of interrelated angiogenic, hyperpermeability and vasodilator factors in the feto-maternal interface in pregnant guinea-pigs. Methods Utero-placental units were collected from early to term pregnancy. VEGF, Flt-1, KDR, B2R and eNOS were analyzed by immunohistochemistry, and the intensity of the signals in placenta and syncytial streamers was digitally analysed. Flt1 and eNOS content of placental homogenates was determined by western blotting. Statistical analysis used one-way analysis of variance and Tukey's Multiple Comparison post-hoc test. Results In the subplacenta, placental interlobium and labyrinth VEGF, Flt-1, KDR, B2R and eNOS were expressed in all stages of pregnancy. Syncytial streamers in all stages of gestation, and cytotrophoblasts surrounding myometrial arteries in early and mid pregnancy – and replacing the smooth muscle at term – displayed immunoreactivity for VEGF, Flt-1, KDR, eNOS and B2R. In partly disrupted mesometrial arteries in late pregnancy cytotrophoblasts and endothelial cells expressed VEGF, Flt-1, KDR, B2R and eNOS. Sections incubated in absence of the first antibody, or in presence of rabbit IgG fraction and mouse IgG serum, yielded no staining. According to the digital analysis, Flt-1 increased in the placental interlobium in days 40 and 60 as compared to day 20 (P = 0.016), and in the labyrinth in day 60 as compared to days 20 and 40 (P = 0.026), while the signals for VEGF, KDR, B2R, and eNOS showed no variations along pregnancy. In syncytial streamers the intensity of VEGF immunoreactivity was increased in day 40 in comparison to day 20 (P = 0.027), while that of B2R decreased in days 40 and 60 as compared to day 20 (P = 0.011); VEGF, Flt-1, KDR, B2R and eNOS expression showed no variations. Western blots for eNOS and Flt-1 in placental homogenates showed no significant temporal differences along pregnancy. Conclusion The demonstration of different angiogenic, hyperpermeability and vasodilator factors in the same cellular protagonists of angiogenesis and invasion in the pregnant guinea-pig, supports the presence of a functional network, and strengthens the argument that this species provides an adequate model to understand human pregnancy.Abstract Background The angiogenic and invasive properties of the cytotrophoblast are crucial to provide an adequate area for feto-maternal exchange. The present study aimed at identifying the localization of interrelated angiogenic, hyperpermeability and vasodilator factors in the feto-maternal interface in pregnant guinea-pigs. Methods Utero-placental units were collected from early to term pregnancy. VEGF, Flt-1, KDR, B2R and eNOS were analyzed by immunohistochemistry, and the intensity of the signals in placenta and syncytial streamers was digitally analysed. Flt1 and eNOS content of placental homogenates was determined by western blotting. Statistical analysis used one-way analysis of variance and Tukey's Multiple Comparison post-hoc test. Results In the subplacenta, placental interlobium and labyrinth VEGF, Flt-1, KDR, B2R and eNOS were expressed in all stages of pregnancy. Syncytial streamers in all stages of gestation, and cytotrophoblasts surrounding myometrial arteries in early and mid pregnancy – and replacing the smooth muscle at term – displayed immunoreactivity for VEGF, Flt-1, KDR, eNOS and B2R. In partly disrupted mesometrial arteries in late pregnancy cytotrophoblasts and endothelial cells expressed VEGF, Flt-1, KDR, B2R and eNOS. Sections incubated in absence of the first antibody, or in presence of rabbit IgG fraction and mouse IgG serum, yielded no staining. According to the digital analysis, Flt-1 increased in the placental interlobium in days 40 and 60 as compared to day 20 (P = 0.016), and in the labyrinth in day 60 as compared to days 20 and 40 (P = 0.026), while the signals for VEGF, KDR, B2R, and eNOS showed no variations along pregnancy. In syncytial streamers the intensity of VEGF immunoreactivity was increased in day 40 in comparison to day 20 (P = 0.027), while that of B2R decreased in days 40 and 60 as compared to day 20 (P = 0.011); VEGF, Flt-1, KDR, B2R and eNOS expression showed no variations. Western blots for eNOS and Flt-1 in placental homogenates showed no significant temporal differences along pregnancy. Conclusion The demonstration of different angiogenic, hyperpermeability and vasodilator factors in the same cellular protagonists of angiogenesis and invasion in the pregnant guinea-pig, supports the presence of a functional network, and strengthens the argument that this species provides an adequate model to understand human pregnancy.Abstract Background The angiogenic and invasive properties of the cytotrophoblast are crucial to provide an adequate area for feto-maternal exchange. The present study aimed at identifying the localization of interrelated angiogenic, hyperpermeability and vasodilator factors in the feto-maternal interface in pregnant guinea-pigs. Methods Utero-placental units were collected from early to term pregnancy. VEGF, Flt-1, KDR, B2R and eNOS were analyzed by immunohistochemistry, and the intensity of the signals in placenta and syncytial streamers was digitally analysed. Flt1 and eNOS content of placental homogenates was determined by western blotting. Statistical analysis used one-way analysis of variance and Tukey's Multiple Comparison post-hoc test. Results In the subplacenta, placental interlobium and labyrinth VEGF, Flt-1, KDR, B2R and eNOS were expressed in all stages of pregnancy. Syncytial streamers in all stages of gestation, and cytotrophoblasts surrounding myometrial arteries in early and mid pregnancy – and replacing the smooth muscle at term – displayed immunoreactivity for VEGF, Flt-1, KDR, eNOS and B2R. In partly disrupted mesometrial arteries in late pregnancy cytotrophoblasts and endothelial cells expressed VEGF, Flt-1, KDR, B2R and eNOS. Sections incubated in absence of the first antibody, or in presence of rabbit IgG fraction and mouse IgG serum, yielded no staining. According to the digital analysis, Flt-1 increased in the placental interlobium in days 40 and 60 as compared to day 20 (P = 0.016), and in the labyrinth in day 60 as compared to days 20 and 40 (P = 0.026), while the signals for VEGF, KDR, B2R, and eNOS showed no variations along pregnancy. In syncytial streamers the intensity of VEGF immunoreactivity was increased in day 40 in comparison to day 20 (P = 0.027), while that of B2R decreased in days 40 and 60 as compared to day 20 (P = 0.011); VEGF, Flt-1, KDR, B2R and eNOS expression showed no variations. Western blots for eNOS and Flt-1 in placental homogenates showed no significant temporal differences along pregnancy. Conclusion The demonstration of different angiogenic, hyperpermeability and vasodilator factors in the same cellular protagonists of angiogenesis and invasion in the pregnant guinea-pig, supports the presence of a functional network, and strengthens the argument that this species provides an adequate model to understand human pregnancy.Abstract Background The angiogenic and invasive properties of the cytotrophoblast are crucial to provide an adequate area for feto-maternal exchange. The present study aimed at identifying the localization of interrelated angiogenic, hyperpermeability and vasodilator factors in the feto-maternal interface in pregnant guinea-pigs. Methods Utero-placental units were collected from early to term pregnancy. VEGF, Flt-1, KDR, B2R and eNOS were analyzed by immunohistochemistry, and the intensity of the signals in placenta and syncytial streamers was digitally analysed. Flt1 and eNOS content of placental homogenates was determined by western blotting. Statistical analysis used one-way analysis of variance and Tukey's Multiple Comparison post-hoc test. Results In the subplacenta, placental interlobium and labyrinth VEGF, Flt-1, KDR, B2R and eNOS were expressed in all stages of pregnancy. Syncytial streamers in all stages of gestation, and cytotrophoblasts surrounding myometrial arteries in early and mid pregnancy – and replacing the smooth muscle at term – displayed immunoreactivity for VEGF, Flt-1, KDR, eNOS and B2R. In partly disrupted mesometrial arteries in late pregnancy cytotrophoblasts and endothelial cells expressed VEGF, Flt-1, KDR, B2R and eNOS. Sections incubated in absence of the first antibody, or in presence of rabbit IgG fraction and mouse IgG serum, yielded no staining. According to the digital analysis, Flt-1 increased in the placental interlobium in days 40 and 60 as compared to day 20 (P = 0.016), and in the labyrinth in day 60 as compared to days 20 and 40 (P = 0.026), while the signals for VEGF, KDR, B2R, and eNOS showed no variations along pregnancy. In syncytial streamers the intensity of VEGF immunoreactivity was increased in day 40 in comparison to day 20 (P = 0.027), while that of B2R decreased in days 40 and 60 as compared to day 20 (P = 0.011); VEGF, Flt-1, KDR, B2R and eNOS expression showed no variations. Western blots for eNOS and Flt-1 in placental homogenates showed no significant temporal differences along pregnancy. Conclusion The demonstration of different angiogenic, hyperpermeability and vasodilator factors in the same cellular protagonists of angiogenesis and invasion in the pregnant guinea-pig, supports the presence of a functional network, and strengthens the argument that this species provides an adequate model to understand human pregnancy.
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    Bradykinin promotes migration and invasion of human immortalized trophoblasts
    (2011) Erices, Rafaela.; Corthorn H., Jenny; Lisboa, Francisco.; Valdés Stromilli, Gloria
    Abstract Having demonstrated that the bradykinin B2 receptor (B2R) is expressed in cells that participate in trophoblast invasion in humans and guinea-pigs, we investigated the role of bradykinin (BK) on cell migration and invasion in the HTR-8/SVneo trophoblast cell line using wound healing and invasion assays. First, we documented that HTR-8/SVneo cells expressed kallikrein, B2R, B1R, MMP-2 and MMP-9 using immunocytochemistry. Incubation with BK (10.0 microMol/L) for 18 hours increased the migration index 3-fold in comparison to controls or to cells preincubated with the B2R antagonist HOE-140. BK (10.0 microMol/L) incubation yielded a similar number of proliferating and viable cells as controls, therefore the enhanced closure of the wound cannot be attributed to proliferating cells. Incubation with BK (10.0 microMol/L) for 18 hours increased the invasion index 2-fold in comparison to controls or to cells preincubated with the antagonist of the B2R. Neither the B1R ligand Lys-des-Arg9 BK, nor its antagonist Lys-(des-Arg9-Leu8), modified migration and invasion. Further support for the stimulatory effect of B2R activation on migration and invasion is provided by the 3-fold increase in the number of filopodia per cell versus controls or cells preincubated with the B2R antagonist. Bradykinin had no effect on the cellular protein content of the B2R, nor the MMP-9 and MMP-2 gelatinase activity in the culture media varied after incubation with BK. This study adds bradykinin-acting on the B2R-to the stimuli of trophoblast migration and invasion, an effect that should be integrated to other modifications of the kallikrein-kinin system in normal and pathological pregnancies.
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    Polarity of kallikrein release and activation in perfused rat kidneys
    (1990) Boric P., Mauricio; Corthorn H., Jenny; Roblero S., Juan
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    Spatio-temporal expression of MMP-2, MMP-9 and tissue kallikrein in uteroplacental units of the pregnant guinea-pig (Cavia porcellus)
    (2007) Corthorn H., Jenny; Rey Keim, Sergio; Chacón Figueroa, Cynthia Cecilia.; Valdés Stromilli, Gloria
    Abstract Background In humans trophoblast invasion and vascular remodeling are critical to determine the fate of pregnancy. Since guinea-pigs share with women an extensive migration of the trophoblasts through the decidua and uterine arteries, and a haemomonochorial placenta, this species was used to evaluate the spatio-temporal expression of three enzymes that have been associated to trophoblast invasion, MMP-2, MMP-9 and tissue kallikrein (K1). Methods Uteroplacental units were collected from early to term pregnancy. MMP-2, MMP-9 and K1 were analysed by immunohistochemistry and Western blot. The activities of MMP-2 and MMP-9 were assessed by gelatin zymography. Results Immunoreactive MMP-2, MMP-9 and K1 were detected in the subplacenta, interlobar and labyrinthine placenta, syncytial sprouts and syncytial streamers throughout pregnancy. In late pregnancy, perivascular or intramural trophoblasts expressed the three enzymes. The intensity of the signal in syncytial streamers was increased in mid and late pregnancy for MMP-2, decreased in late pregnancy for MMP-9, and remained stable for K1. Western blots of placental homogenates at days 20, 40 and 60 of pregnancy identified bands with the molecular weights of MMP-2, MMP-9 and K1. MMP-2 expression remained constant throughout gestation. In contrast, MMP-9 and K1 attained their highest expression during midgestation. Placental homogenates of 20, 40 and 60 days yielded bands of gelatinase activity that were compatible with MMP-2 and MMP-9 activities. ProMMP-2 and MMP-9 activities did not vary along pregnancy, while MMP-2 and MMP-9 increased at 40 and 40–60 days respectively. Conclusion The spatio-temporal expression of MMPs and K1 supports a relevant role of these proteins in trophoblast invasion, vascular remodeling and placental angiogenesis, and suggests a functional association between K1 and MMP-9 activation.
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    Utero-placental expression of angiotensin-(1-7) and ACE2 in the pregnant guinea-pig
    (2013) Valdés Stromilli, Gloria; Corthorn H., Jenny; Schneider, Daniela.; Bharadwaj, Manish S.; Joyner-Grantham, JaNae.; Brosnihan, K. Bridget.
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    Vasodilator factors in the systemic and local adaptations to pregnancy
    (2009) Valdés Stromilli, Gloria; Kaufmann, Peter; Corthorn H., Jenny; Erices, Rafaela; Brosnihan, K B; Joyner-Grantham, JaNae
    Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.Abstract We postulate that an orchestrated network composed of various vasodilatory systems participates in the systemic and local hemodynamic adaptations in pregnancy. The temporal patterns of increase in the circulating and urinary levels of five vasodilator factors/systems, prostacyclin, nitric oxide, kallikrein, angiotensin-(1–7) and VEGF, in normal pregnant women and animals, as well as the changes observed in preeclamptic pregnancies support their functional role in maintaining normotension by opposing the vasoconstrictor systems. In addition, the expression of these vasodilators in the different trophoblastic subtypes in various species supports their role in the transformation of the uterine arteries. Moreover, their expression in the fetal endothelium and in the syncytiotrophoblast in humans, rats and guinea-pigs, favour their participation in maintaining the uteroplacental circulation. The findings that sustain the functional associations of the various vasodilators, and their participation by endocrine, paracrine and autocrine regulation of the systemic and local vasoactive changes of pregnancy are abundant and compelling. However, further elucidation of the role of the various players is hampered by methodological problems. Among these difficulties is the complexity of the interactions between the different factors, the likelihood that experimental alterations induced in one system may be compensated by the other players of the network, and the possibility that data obtained by manipulating single factors in vitro or in animal studies may be difficult to translate to the human. In addition, the impossibility of sampling the uteroplacental interface along normal pregnancy precludes obtaining longitudinal profiles of the various players. Nevertheless, the possibility of improving maternal blood pressure regulation, trophoblast invasion and uteroplacental flow by enhancing vasodilation (e.g. L-arginine, NO donors, VEGF transfection) deserves unravelling the intricate association of vasoactive factors and the systemic and local adaptations to pregnancy.