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The role of the Angiopoietin-1 (Ang1)-Tie2 pathway in pulmonary arterial hypertension (PAH) is controversial, with one group suggesting that increased Ang1-Tie2 activity may even play a causal role in PAH progression. However, Ang1 has been well-characterized as a homeostatic factor, which prevents endothelial cell (EC) activation and injury through Tie2 receptor stimulation. Furthermore, we have previously demonstrated that lung Tie2 expression and activity are significantly downregulated in experimental PAH, implicating reduced Tie2 signaling in the pathogenesis of this disease. Thus, we hypothesized that manipulations to increase Ang1-Tie2 signaling will protect against lung EC injury and onset of PAH, whereas a loss-of-function of this pathway in Tie2-deficient mice (Tie2+/-) would predispose to PAH. Approximately 13% of Tie2+/- mice developed spontaneous elevation in right ventricular systolic pressure (RVSP), although no significant difference was observed between the WT and Tie2+/- groups following chronic hypoxic exposure. Serotonin (5-HT) infusion for one week or daily interleukin-6 (IL-6) injection for two weeks produced substantial RVSP elevations in Tie2+/-, but not WT mice (P<0.05). Following one week of 5-HT or IL-6 treatment, there was a significant decrease in Ang1 protein expression in both WT and Tie2+/- mice (P<0.05). Similarly, following exposure of cultured pulmonary arterial smooth muscle cells to 5-HT or IL-6, Ang1 secretion was significantly decreased (P<0.01). Moreover, 5-HT or IL-6 exposure resulted in decreased Tie2 activity and increased apoptosis only in the lungs of Tie2+/- mice (P<0.01), and treatment with a pan-caspase inhibitor, Z-VAD, prevented PAH in 5-HT-treated Tie2-deficient mice. Together with in vitro studies showing that pulmonary arterial ECs subjected to Tie2-siRNA were more susceptible to apoptosis following 5-HT treatment, this strongly implicates EC death as a primary mechanism of PAH in the presence of reduced Tie2 activity. In addition, doxycycline-conditional, endothelial-targeted Ang1 binary transgenic mice showed no evidence of elevated RVSP under basal conditions and if anything, demonstrated a blunted response to 5-HT treatment compared to non-binary littermate controls. Therefore, our findings support the importance of EC survival-signaling via the Ang1-Tie2 pathway as a protective mechanism in PAH and emphasize the pivotal role of EC apoptosis in the onset of this disease.

The role of the Angiopoietin-1 (Ang1)-Tie2 pathway in pulmonary arterial hypertension (PAH) is controversial, with one group suggesting that increased Ang1-Tie2 activity may even play a causal role in PAH progression. However, Ang1 has been well-characterized as a homeostatic factor, which prevents endothelial cell (EC) activation and injury through Tie2 receptor stimulation. Furthermore, we have previously demonstrated that lung Tie2 expression and activity are significantly downregulated in experimental PAH, implicating reduced Tie2 signaling in the pathogenesis of this disease. Thus, we hypothesized that manipulations to increase Ang1-Tie2 signaling will protect against lung EC injury and onset of PAH, whereas a loss-of-function of this pathway in Tie2-deficient mice (Tie2+/-) would predispose to PAH. Approximately 13% of Tie2+/- mice developed spontaneous elevation in right ventricular systolic pressure (RVSP), although no significant difference was observed between the WT and Tie2+/- groups following chronic hypoxic exposure. Serotonin (5-HT) infusion for one week or daily interleukin-6 (IL-6) injection for two weeks produced substantial RVSP elevations in Tie2+/-, but not WT mice (P<0.05). Following one week of 5-HT or IL-6 treatment, there was a significant decrease in Ang1 protein expression in both WT and Tie2+/- mice (P<0.05). Similarly, following exposure of cultured pulmonary arterial smooth muscle cells to 5-HT or IL-6, Ang1 secretion was significantly decreased (P<0.01). Moreover, 5-HT or IL-6 exposure resulted in decreased Tie2 activity and increased apoptosis only in the lungs of Tie2+/- mice (P<0.01), and treatment with a pan-caspase inhibitor, Z-VAD, prevented PAH in 5-HT-treated Tie2-deficient mice. Together with in vitro studies showing that pulmonary arterial ECs subjected to Tie2-siRNA were more susceptible to apoptosis following 5-HT treatment, this strongly implicates EC death as a primary mechanism of PAH in the presence of reduced Tie2 activity. In addition, doxycycline-conditional, endothelial-targeted Ang1 binary transgenic mice showed no evidence of elevated RVSP under basal conditions and if anything, demonstrated a blunted response to 5-HT treatment compared to non-binary littermate controls. Therefore, our findings support the importance of EC survival-signaling via the Ang1-Tie2 pathway as a protective mechanism in PAH and emphasize the pivotal role of EC apoptosis in the onset of this disease.

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The effects of a twelve-week low-intensity exercise conditioning program on blood pressure (BP), heart rate (HR), rate-pressure-product (RPP) and cardiac autonomic function were examined in menopausal and post menopausal women with hypertension. Eligible participants (n=50) were counterbalanced to either the exercise group or the control group. Using a pretest-posttest design, participants were tested at the beginning and the end of the 12-week study period, in which BP, HR, RPP, heart rate variability and spontaneous baroreflex sensitivity were measured at rest and during standing and low intensity steady-state exercise. The exercise group participated in a 12-week, low-intensity walking program, 5 days/week, while the comparison group continued with usual activity. The exercise group adhered to 4 walking sessions per week while the control group averaged 0.6 walking sessions per week. Repeated measures analysis of variance (ANOVA) demonstrated a reduction in systolic and diastolic BP and RPP in hypertensive women. Additionally, the low intensity exercise conditioning program attenuated the physiological response to stress (standing, exercise). This was evidenced by decreased systolic and diastolic BP and RPP in the exercise group and increased diastolic BP in the control group. Postmenopausal women demonstrated decreased log transformed high frequency power and total power in comparison to menopausal women. However, postmenopausal women also showed decreased low frequency power in comparison to menopausal women. It was concluded that a 12-week, low-intensity exercise conditioning program reduced systolic and diastolic BP and RPP in hypertensive women while attenuating their physiological responses to stress. / Thesis (Master, Nursing) -- Queen's University, 2008-09-25 21:46:53.32

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Background: Preliminary observations suggest that aberrations in maternal central hemodynamics and uterine artery Doppler velocimetry reflect the severity of hypertensive disorders of pregnancy. In addition, the precise changes of cardiac output in normal pregnancy, particularly in the third trimester, have remained controversial. Aims and Objective: To measure concomitantly Doppler echocardiographic maternal central hemodynamics and uterine artery Doppler velocimetry and evaluate their association with adverse feto-neonatal outcome in hypertensive pregnant women. To evaluate cardiac output longitudinally in the latter half of pregnancy in normal healthy women. Design and Setting: Prospective study conducted at the Obstetric Unit, King Edward VIII Hospital, Durban, South Africa. Study sample: forty (40) pregnant hypertensives without any prior therapy and a further group of pre-eclamptic women (n=22) treated with stat dose sodium gardinal and alpha-methyldopa were studied. Results: i) A trend to a higher cardiac output was seen in the hypertensives compared to the normotensives. Hypertensive women were of larger stature; there was no difference in cardiac index. Fetal birthweight correlated poorly with cardiac index in pre-eclamptic women (r =0.21). A better correlation was seen with uterine artery resistance index (r = - 0.65) and systemic vascular resistance index (r = -0.49). Critical values for cardiac index and systemic vascular resistance index to predict poor adverse feto-neonatal outcome with good predictive values were not identified. ii) Pre-eclamptics treated with stat dose of sodium gardinal and/or methyldopa prior to echocardiography had a significantly lower systemic vascular resistance index and uterine artery resistance index compared to the untreated group. The lower systemic vascular resistance index in this treated cohort occurred from a combination of non-significant lower blood pressure and higher cardiac index. iii) Compared to normotensive women, untreated pre-eclamptics had a significantly lower heart rate (p< 0.001), a higher stroke index (p=0.018) and no difference in resultant cardiac index (p=0.452). iv) In gestational apoteinuric hypertensives presenting after 34 weeks gestation, maternal hemodynamics and uterine artery resistance index did not help define a higher risk group. v) In chronic hypertensives pregnancies, left ventricular hypertrophy correlated with severity of blood pressure. Higher risk chronic hypertensives were better selected by proteinuria than maternal central hemodynamics or uterine artery resistance index. vi) In normal pregnancy, maternal cardiac output peaked in early to mid third trimester and was maintained till term. Significant correlations were observed among maternal cardiac output, maternal body surface area and fetal birth weight. Discussion: i) This study shows that cardiac index and systemic vascular resistance index measured in the latter part of the second and third trimesters in hypertensive pregnant women were not associated with adverse fetal outcome. Large variations in cardiac index values were observed that restricted detection of satisfactory critical values for cardiac index and systemic vascular resistance index to predict adverse outcome. ii) An improved correlation of uterine artery resistance index with maternal hemodynamics and fetal birthweight in pre-eclampsia supports the hypothesis that poor placentation does not allow for a normal increase in uterine blood flow. iii) The poor correlation between uterine artery resistance index and maternal central hemodynamics, does not support the hypothesis that elevated cardiac output in hypertensive pregnancies (hyperdynamic disease model) occurs as a compensatory response to maintain adequate perfusion in a utero-placental bed with high resistance that did not decrease. / Thesis (Ph.D.)-University of KwaZulu-Natal, Durban, 2004.

Hypertension is accompanied by structural and mechanical abnormalities in resistance arteries. The effects of resveratrol, a phenolic phytoalexin found naturally in various foods, on systolic blood pressure and resistance artery structure and stiffness were assessed in spontaneously hypertensive rats (SHRs). Vascular geometry and mechanical properties of pressurized mesenteric resistance arteries were calculated from media and lumen dimensions measured using pressure myography. Compared to normotensive Wistar-Kyoto (WKY) rats, resistance arteries from SHRs displayed remodeling with narrowed lumen diameters (246.2±21.0 vs. 308.1±14.3 μm, p<0.05), thickened media widths (39.8±4.6 vs. 28.5±2.7 μm, p<0.05) and augmented media-to-lumen ratios (17.7±2.6 vs. 9.3±1.0, p<0.05). Calculations of remodeling and growth indices revealed that SHR vessels underwent mostly eutrophic remodeling. Systolic blood pressure was elevated in 20-week-old SHR versus WKY rats (219±6 vs. 155±6 mmHg, p<0.01) and was unaffected by resveratrol (2.5 mg/Kg/d). In SHRs, resveratrol treatment attenuated eutrophic remodeling and normalized increased vessel compliance (p<0.01) as determined by a restorative leftward shift in the stress-strain curve of SHR arteries (p<0.01). Resveratrol treatment restored stiffness in SHRs (4.2±0.4 vs. 6.6±0.5, p<0.05) through the normalization of vessel geometry. Immunoblotting revealed that resveratrol negated typical pronounced ERK1/2 signaling in SHR arteries. Thus, the results of this study suggest that resveratrol restores vascular mechanical properties in SHRs and attenuates remodeling. Furthermore the attenuation of remodeling in SHR arteries with resveratrol treatment is associated with the inhibition of ERK1/2 activity.

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