RESUMO
This work was designed to study the expression of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] and its generating enzyme (ACE2) in the uteroplacental interface. Placentas were obtained from 11 early pregnancy failures (5 miscarriages and 6 ectopic pregnancies), 15 normotensive, and 10 preeclamptic gestations. In placental villi, the main sites of immunocytochemical expression of Ang-(1-7) and ACE2 were the syncytiotrophoblast, cytotrophoblast, endothelium and vascular smooth muscle of primary and secondary villi. Syncitial Ang-(1-7) expression in samples obtained from miscarriages and ectopic pregnancies was increased compared to normal term pregnancy [2.0 (2.0-2.25 for the 25 and 75% interquartile range) vs 1.3 (1.0-1.9), p<0.01]. In the maternal stroma, Ang-(1-7) and ACE2 were expressed in the invading and intravascular trophoblast and in decidual cells in all 3 groups. Ang-(1-7) and ACE2 staining was also found in arterial and venous endothelium and smooth muscle of the umbilical cord. The expression of Ang-(1-7) and ACE2 was similar in samples obtained from normal term or preeclamptic pregnancies, except for increased expression of ACE2 in umbilical arterial endothelium in preeclampsia [0.5 (0.5-0.8) vs 0.0 (0.0-0.0), p<0.01]. The uteroplacental location of Ang-(1-7) and ACE2 in pregnancy suggests an autocrine function of Ang-(1-7) in the vasoactive regulation that characterizes placentation and established pregnancy.
Assuntos
Angiotensina I/análise , Carboxipeptidases/análise , Fragmentos de Peptídeos/análise , Placenta/química , Complicações na Gravidez/metabolismo , Gravidez/metabolismo , Angiotensina I/metabolismo , Enzima de Conversão de Angiotensina 2 , Carboxipeptidases/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A , Placenta/enzimologia , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Complicações na Gravidez/enzimologiaRESUMO
Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS). The physiological consequences of the stimulated RAS in normal pregnancy are incompletely understood, and even less understood is the question of how this system may be altered and contribute to the hypertensive disorders of pregnancy. Findings from our group have provided novel insights into how the RAS may contribute to the physiological condition of pregnancy by showing that pregnancy increases the expression of both the vasodilator heptapeptide of the RAS, angiotensin-(1-7) [Ang-(1-7)], and of a newly cloned angiotensin converting enzyme (ACE) homolog, ACE2, that shows high catalytic efficiency for Ang II metabolism to Ang-(1-7). The discovery of ACE2 adds a new dimension to the complexity of the RAS by providing a new arm that may counter-regulate the activity of the vasoconstrictor component, while amplifying the vasodilator component. The studies reviewed in this article demonstrate that Ang-(1-7) increases in plasma and urine of normal pregnant women. In preeclamptic subjects we showed that plasma Ang-(1-7) was suppressed as compared to the levels found in normal pregnancy. In addition, kidney and urinary levels of Ang-(1-7) were increased in pregnant rats coinciding with the enhanced detection and expression of ACE2. These findings support the concept that in normal pregnancy enhanced ACE2 may counteract the elevation in tissue and circulating Ang II by increasing the rate of conversion to Ang-(1-7). These findings provide a basis for the physiological role of Ang-(1-7) and ACE2 during pregnancy.
Assuntos
Humanos , Animais , Feminino , Gravidez , Ratos , Angiotensina I , Peptidil Dipeptidase A , Pré-Eclâmpsia , Sistema Renina-Angiotensina , BiomarcadoresRESUMO
Pregnancy is a physiological condition characterized by a progressive increase of the different components of the renin-angiotensin system (RAS). The physiological consequences of the stimulated RAS in normal pregnancy are incompletely understood, and even less understood is the question of how this system may be altered and contribute to the hypertensive disorders of pregnancy. Findings from our group have provided novel insights into how the RAS may contribute to the physiological condition of pregnancy by showing that pregnancy increases the expression of both the vasodilator heptapeptide of the RAS, angiotensin-(1-7) [Ang-(1-7)], and of a newly cloned angiotensin converting enzyme (ACE) homolog, ACE2, that shows high catalytic efficiency for Ang II metabolism to Ang-(1-7). The discovery of ACE2 adds a new dimension to the complexity of the RAS by providing a new arm that may counter-regulate the activity of the vasoconstrictor component, while amplifying the vasodilator component. The studies reviewed in this article demonstrate that Ang-(1-7) increases in plasma and urine of normal pregnant women. In preeclamptic subjects we showed that plasma Ang-(1-7) was suppressed as compared to the levels found in normal pregnancy. In addition, kidney and urinary levels of Ang-(1-7) were increased in pregnant rats coinciding with the enhanced detection and expression of ACE2. These findings support the concept that in normal pregnancy enhanced ACE2 may counteract the elevation in tissue and circulating Ang II by increasing the rate of conversion to Ang-(1-7). These findings provide a basis for the physiological role of Ang-(1-7) and ACE2 during pregnancy.
Assuntos
Angiotensina I/metabolismo , Fragmentos de Peptídeos/metabolismo , Peptidil Dipeptidase A/metabolismo , Pré-Eclâmpsia/sangue , Gravidez/metabolismo , Sistema Renina-Angiotensina/fisiologia , Angiotensina I/sangue , Angiotensina I/urina , Animais , Biomarcadores , Feminino , Humanos , Fragmentos de Peptídeos/sangue , Fragmentos de Peptídeos/urina , Peptidil Dipeptidase A/sangue , Peptidil Dipeptidase A/urina , Gravidez/sangue , Gravidez/urina , RatosRESUMO
Since normal human pregnancy is characterized by normotension in the face of an increased renin-angiotensin-aldosterone system (RAAS), we evaluated the temporal pattern of urinary excretion of a novel vasodilator within this system, angiotensin-(1-7) (Ang-[1-7]), during the menstrual cycle, pregnancy, and lactation. The urinary profiles of Ang I, Ang II, human chorionic gonadotropin, 17beta-estradiol, and progesterone were also determined. During the menstrual cycle, urinary Ang-(1-7) and Ang II remained stable (mean cycle value: 94.6 +/- 11.3 and 11.4 +/- 1.1 pmol/g of creatinine, respectively) in nine females. In 10 normal pregnant women, urinary Ang-(1-7) and Ang II increased throughout gestation, averaging 1499.8 +/- 310 and 224.4 +/- 58 pmol/g of creatinine, respectively (p < 0.05) at wk 35 and falling during lactation to 394.0 +/- 95 and 65.7 +/- 20 pmol/ g of creatinine (p < 0.05), respectively. The Ang-(1-7)/Ang II ratio was unchanged in the different reproductive periods. During the menstrual cycle, Ang II and Ang-(1-7) correlated with 17beta-estradiol and progesterone using multivariate analysis (r = 0.31, p < 0.001) and r = 0.28, p < 0.02, respectively). During gestation, 17beta-estradiol and progesterone correlated with urinary Ang-(1-7) (r = 0.48, p < 0.001 and r = 0.47, p < 0.001, respectively) and Ang II (r = 0.24, p < 0.03 and r = 0.25, p < 0.03, respectively); by multiple regression, only Ang-(1-7) correlated with both steroids (r = 0.49,p < 0.001). The progressive rise of Ang-(1-7) throughout gestation, probably modulated by estrogen and progesterone, suggests a physiologic counterregulation within the RAAS.
Assuntos
Angiotensinas/fisiologia , Lactação/urina , Ciclo Menstrual/urina , Gravidez/urina , Vasoconstrição/fisiologia , Vasodilatação/fisiologia , Adulto , Angiotensina I/fisiologia , Angiotensina I/urina , Angiotensina II/fisiologia , Angiotensina II/urina , Angiotensinas/urina , Feminino , Humanos , Fragmentos de Peptídeos/fisiologia , Fragmentos de Peptídeos/urinaRESUMO
Estrogen stimulates the renin-angiotensin system by augmenting both tissue and circulating levels of angiotensinogen and renin. We show, however, that angiotensin converting enzyme (ACE) activity in the circulation and in tissues is reduced in two animal models of postmenopausal chronic hormone replacement. We observed a reduction of ACE activity in association with a significant increase in plasma angiotensin I (Ang I) and hyperreninemia in ovariectomized monkeys treated with Premarin (conjugated equine estrogen) replacement for 30 months. Plasma angiotensin II (Ang II) levels were not increased in monkeys treated with estrogen, suggesting that the decrease in ACE curtailed the formation of the peptide. The Ang II/Ang I ratio, an in vivo index of ACE activity, was significantly reduced by estrogen treatment, further supporting the biochemical significance of estrogen's inhibition of ACE. In ovariectomized transgenic hypertensive (mRen2)27 rats submitted to estrogen replacement treatment for 3 weeks, ACE activity in plasma and tissue (aorta and kidney) and circulating Ang II levels were reduced, whereas circulating levels of angiotensin-(1-7) (Ang-(1-7)) were increased. Ang-(1-7), the N-terminal fragment of Ang II, is a novel vasodilator and antihypertensive peptide. Thus, the net balance of these effects of estrogen on the reninangiotensin vasoconstrictor/vasodilator system is to promote the anti-hypertensive effect.
Assuntos
Estrogênios/fisiologia , Sistema Renina-Angiotensina/fisiologia , Angiotensinas/análise , Animais , Aorta Torácica/enzimologia , Terapia de Reposição de Estrogênios , Feminino , Haplorrinos , Rim/enzimologia , Ovariectomia , Peptidil Dipeptidase A , Plasma/enzimologia , Ratos , Vasoconstritores/análiseRESUMO
Estrogen stimulates the renin-angiotensin system by augmenting both tissue and circulating levels of angiotensinogen and renin. We show, however, that angiotensin converting enzyme (ACE) activity in the circulation and in tissues is reduced in two animal models of postmenopausal chronic hormone replacement. We observed a reduction of ACE activity in association with a significant increase in plasma angiotensin I (Ang I) and hyperreninemia in ovariectomized monkeys treated with Premarin (conjugated equine estrogen) replacement for 30 months. Plasma angiotensin II (Ang II) levels were not increased in monkeys treated with estrogen, suggesting that the decrease in ACE curtailed the formation of the peptide. The Ang II/Ang I ratio, an in vivo index of ACE activity, was significantly reduced by estrogen treatment, further supporting the biochemical significance of estrogen's inhibition of ACE. In ovariectomized transgenic hypertensive (mRen2)27 rats submitted to estrogen replacement treatment for 3 weeks, ACE activity in plasma and tissue (aorta and kidney) and circulating Ang II levels were reduced, whereas circulating levels of angiotensin-(1-7) (Ang-(1-7) were increased. Ang-(1-7), the N-terminal fragment of Ang II, is a novel vasodilator and antihypertensive peptide. Thus, the net balance of these effects of estrogen on the renin-angiotensin vasoconstrictor/vasodilator system is to promote the antihypertensive effect.
Assuntos
Animais , Feminino , Ratos , Estrogênios/metabolismo , Sistema Renina-Angiotensina/fisiologia , Angiotensinas/análise , Angiotensinas/efeitos dos fármacos , Aorta Torácica/enzimologia , Terapia de Reposição de Estrogênios , Estrogênios/farmacologia , Haplorrinos , Rim/enzimologia , Ovariectomia , Peptidil Dipeptidase A , Plasma/enzimologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Vasoconstritores/análiseRESUMO
Angiotensin-(1-7) [Ang-(1-7)] possesses novel biological functions that are distinct from angiotensin II (Ang II). In coronary arteries, the octapeptide Ang II and the heptapeptide Ang-(1-7) exert opposing actions. Ang II elicits vasoconstriction and Ang-(1-7) is a vasodilator. Ang-(1-7) elicits vasodilation by an endothelium-dependent release of nitric oxide. Further, the vasorelaxant activity is markedly attenuated by the bradykinin (BK) B2 receptor antagonist icatibant and does not appear to be associated with the synthesis and release of prostaglandins. Ang-(1-7) vasodilation is mediated by a non-AT1/AT2 receptor, since [Sar1Thr8]-Ang II, but neither candesartan, an AT1 receptor antagonist, nor PD123319, an AT2 receptor antagonist, blocked the response. Specific and high affinity binding of 125I-Ang-(1-7) to the endothelial layer of canine coronary arteries was demonstrated using in vitro emulsion autoradiography. Binding was effectively competed for by either unlabeled Ang-(1-7) or the specific Ang-(1-7) antagonist [D-Ala7]-Ang-(1-7). Additionally, Ang-(1-7) potentiated synergistically BK-induced vasodilation. The EC50 of BK vasodilation (2.45 +/- 0.51 nmol/L vs 0.37 +/- 0.08 nmol/L) was shifted 6.6-fold left-ward in the presence of 2 mumol/L concentration of Ang-(1-7). The potentiated response was specific for BK, since Ang-(1-7) did not augment the vasodilation produced by either acetylcholine or sodium nitroprusside; further, it was specific for Ang-(1-7), since neither Ang I nor Ang II augmented the BK response. In contrast to the vasodilator actions of Ang-(1-7), the potentiated response was not blocked by candesartan, PD123319 or [Sar1Thr8]-Ang II. Novel studies from our group demonstrate that Ang-(1-7) is both a substrate and inhibitor for angiotensin converting enzyme (ACE). Ang-(1-7) was shown to retard the degradation of 125I-[Tyr0]-BK in coronary rings. These studies describe novel actions of Ang-(1-7) as a vasodilator and a local synergistic modulator of kinin-induced vasodilation in coronary arteries.