Angiotensin II and angiotensin-(1-7) decrease sFlt1 release in normal but not preeclamptic chorionic villi: an in vitro study

<p>Abstract</p> <p>Background</p> <p>During preeclampsia, placental angiogenesis is impaired. Factors released from the placenta including vascular endothelial growth factor (VEGF), placental growth factor (PLGF), soluble VEGF receptor 1 (sFlt1), and soluble endoglin (sEng) are regulatory molecules of placental development and function. While the renin angiotensin system has been shown to regulate angiogenic factors in other research fields, these mechanisms have not been extensively studied during pregnancy.</p> <p>Methods</p> <p>We evaluated the effects of angiotensin II (Ang II) and angiotensin-(1-7) [Ang-(1-7)] on the release of VEGF, PLGF, sFlt1, and sEng from placental chorionic villi (CV). CV were collected from nulliparous third-trimester normotensive and preeclamptic subjects. CV were incubated for 0, 2, 4, and 16 hours with or without Ang II (1 nM and 1 microM) or Ang-(1-7) (1 nM and 1 microM). The release of VEGF, PLGF, sFlt1, sEng, lactate dehydrogenase (LDH), and human placenta lactogen (HPL) was measured by ELISA.</p> <p>Results</p> <p>The release of sFlt1, PLGF, sEng from normal and preeclamptic CV increased over time. Release of sFlt1 and sEng was significantly higher from preeclamptic CV. VEGF was below the detectable level of the assay in normal and preeclamptic CV. After 2 hours, sFlt1 release from normal CV was significantly inhibited with Ang II (1 nM and 1 microM) and Ang-(1-7) (1 nM and 1 microM). There was a time-dependent increase in HPL indicating that the CV were functioning normally.</p> <p>Conclusions</p> <p>Our study demonstrates a critical inhibitory role of angiotensin peptides on sFlt1 in normal pregnancy. Loss of this regulation in preeclampsia may allow sFlt1 to increase resulting in anti-angiogenesis and end organ damage in the mother.</p

Tissue-specific regulation of ACE/ACE2 and AT 1 /AT 2 receptor gene expression by oestrogen in apolipoprotein E/oestrogen receptor-α knock-out mice: Oestrogen regulation of ACE/ACE2 and AT1/AT2

ACE and ACE2 and the AT1 and AT2 receptors are pivotal points of regulation in the renin-angiotensin system. ACE and ACE2 are key enzymes in the formation and degradation of Ang II and Ang-(1-7). Ang II acts at either the AT1 or the AT2 receptor to mediate opposing actions of vasoconstriction/vasodilation. While it is known that estrogen (E2) acts to down-regulate ACE and the AT1 receptors, its regulation of ACE2 and the AT2 receptor and the involvement of a specific estrogen receptor subtype are unknown. To investigate the role of estrogen receptor-α (ERα) in estrogen’s regulation of ACE/ACE2 and AT1/AT2 mRNAs in lung and kidney, ovariectomized female mice lacking apolipoprotein E (ee) with the ERα (AAee) or without the ERα (ααee) were treated with 17-β estradiol (6 µg/day) or placebo for 3 months. ACE,ACE2 and AT1/AT2 receptor mRNAs were measured using reverse transcriptase, real-time polymerase chain reaction (RT/RT-PCR). In the kidney, 17-β estradiol showed 1.7 fold down-regulation of ACE mRNA in AAee mice, with 2.1-fold up-regulation of ACE mRNA in ααee mice. 17-β estradiol showed 1.5 and 1.8 fold down-regulation of ACE2 and AT1 receptor mRNA in AAee mice; this regulation was lost in ααee mice. 17-β estradiol showed marked (81-fold) up-regulation of the AT2 receptor mRNA in AAee mice. In the lung 17-β estradiol treatment had no effect on AT1 receptor mRNA in AAee mice, but resulted in a 1.5-fold decreased regulation of AT1 mRNA in ααee. There was no significant interaction of estrogen with ER in the lung for ACE, ACE2, and AT2 receptor genes. These studies reveal tissue specific regulation by 17-β estradiol of ACE/ACE2 and AT1/AT2 receptor genes with the ERα receptor primarily responsible for the regulation of kidney ACE2 , AT1 receptor, and AT2 receptor genes

Vasodilator factors in the systemic and local adaptations to pregnancy

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

Phase II Trial of Angiotensin-(1-7) for the Treatment of Patients with Metastatic Sarcoma

Background. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous antiangiogenic hormone with anticancer activity. In a phase I study of Ang-(1-7), two of three patients with metastatic sarcoma experienced disease stabilization. This phase II study examined clinical and biomarker outcomes for patients with metastatic sarcoma. Methods. Ang-(1-7) was administered by subcutaneous injection at a dose of 20 mg daily. If excessive toxicities occurred in the first cohort, a dose deescalation cohort was allowed. Blood samples were obtained to measure changes in biomarkers. Results. Treatment was well-tolerated and the dose deescalation cohort was not required. Plasma PlGF concentrations following treatment were not statistically significantly changed. A significant increase in plasma Ang-(1-7) was observed at 4 hours after injection. The median progression-free survival was 2.7 months (95% CI; 1.4 to 4.1 months), and the median overall survival was 10.2 months (95% CI; 5.3 to 18.3 months). Two patients with vascular sarcomas demonstrated prolonged disease stabilization of 10 months (hemangiopericytoma) and 19 months (epithelioid hemangioendothelioma). Conclusions. Ang-(1-7) at a dose of 20 mg daily was well-tolerated. This prospective phase II study failed to confirm the PlGF biomarker effect identified in the prior phase I study. Prolonged disease stabilization in hemangiopericytoma and epithelioid hemangioendothelioma may warrant further investigation

Cardiovascular Interactions Between Losartan and Fructose in Mice

Aim To determine whether pharmacological blockade of angiotensin (Ang) ATI receptors alters the cardiovascular, metabolic, and angiotensin-converting enzyme (ACE and ACE2) responses to a fructose diet in mice. Methods C57BL male mice were fed with a 60% fructose diet for 8 weeks in combination with losartan treatment on week 9 (30 mg/kg per day). Blood pressure (BP), heart rate (HR), and autonomic balance were monitored using radiotelemetry with spectral analysis. Renal ACE and ACE2 activity and protein levels as well as Ang II and Ang 1-7 were measured. Results Fructose impaired glucose tolerance and increased plasma cholesterol and insulin. These effects were not corrected by losartan treatment. Fructose increased BP and HR but only during the dark period. Short-term losartan treatment decreased BP by 16% in the fructose group but had no effect in controls. This was accompanied by a decrease in BP variance and its low-frequency component. Fructose increased Ang II (plasma and kidney) and ACE 2 (renal activity and protein expression). Losartan alone increased plasma Ang II in plasma and ACE2 in kidney. There were no changes in renal Ang 1-7 levels. Conclusions Losartan reversed the pressor effect of a high fructose diet, demonstrating that there are prominent interactions between a dietary regimen that produces glucose intolerance and an antihypertensive drug that antagonizes Ang signaling. The mechanism of change may be via renal Ang II rather than the ACE2/Ang 1-7 pathway because the fructose losartan combination resulted in lowered renal Ang II without changes in Ang 1-7

Cardiovascular Interactions Between Losartan and Fructose in Mice

Aim To determine whether pharmacological blockade of angiotensin (Ang) ATI receptors alters the cardiovascular, metabolic, and angiotensin-converting enzyme (ACE and ACE2) responses to a fructose diet in mice. Methods C57BL male mice were fed with a 60% fructose diet for 8 weeks in combination with losartan treatment on week 9 (30 mg/kg per day). Blood pressure (BP), heart rate (HR), and autonomic balance were monitored using radiotelemetry with spectral analysis. Renal ACE and ACE2 activity and protein levels as well as Ang II and Ang 1-7 were measured. Results Fructose impaired glucose tolerance and increased plasma cholesterol and insulin. These effects were not corrected by losartan treatment. Fructose increased BP and HR but only during the dark period. Short-term losartan treatment decreased BP by 16% in the fructose group but had no effect in controls. This was accompanied by a decrease in BP variance and its low-frequency component. Fructose increased Ang II (plasma and kidney) and ACE 2 (renal activity and protein expression). Losartan alone increased plasma Ang II in plasma and ACE2 in kidney. There were no changes in renal Ang 1-7 levels. Conclusions Losartan reversed the pressor effect of a high fructose diet, demonstrating that there are prominent interactions between a dietary regimen that produces glucose intolerance and an antihypertensive drug that antagonizes Ang signaling. The mechanism of change may be via renal Ang II rather than the ACE2/Ang 1-7 pathway because the fructose losartan combination resulted in lowered renal Ang II without changes in Ang 1-7