Search

BACKGROUND: Transgender women are individuals born male but identify as female. Many transgender women undergo gender-affirming hormone therapy to alleviate the distress that can occur due to gender incongruence. For transgender women, gender-affirming hormone therapy includes 17β-estradiol (E2) combined with an antiandrogen therapy (AA) or surgical intervention. Numerous studies suggest that the risk of cardiovascular disease is elevated in transgender women; yet, the biological effects of gender-affirming hormone therapy on cardiovascular health are unknown. We hypothesize that a shift in the hormonal milieu versus natal sex in the male rat is associated with an increase in blood pressure at baseline and an enhanced responsiveness to a hypertensive challenge. METHODS: We developed clinically relevant models that mimic gender-affirming hormone therapy combination therapies utilized for the endocrine treatment of gender dysphoria in transgender women. RESULTS: Chronic E2 plus castration or the E2+antiandrogen spironolactone was associated with a significant reduction in lean mass and testosterone. At baseline, 24-hour mean arterial pressure did not differ in E2+castration or E2+antiandrogen therapy versus control, but circadian rhythm was disrupted. In response to chronic Ang II (angiotensin II; 200 ng/kg per minute), the Ang II-induced increase in blood pressure was attenuated in E2+castration compared with control, but the blood pressure response to Ang II was similar in E2+antiandrogen therapy versus control. CONCLUSIONS: Thus, these data indicate that the type of combination therapy utilized may exert differential effects on blood pressure and that disruption of circadian rhythm may be a contributory factor to the increased risk of adverse cardiovascular outcomes in transgender women exposed to high 17β-estradiol coupled to androgen suppression. [ABSTRACT FROM AUTHOR]

The role of adenosine in the regulation of cardiovascular function has long been acknowledged, but only recently has its importance in angiogenesis been appreciated, most notably, through its direct regulation of the proangiogenic growth factor, VEGF. Recent work has established that proangiogenic and antiangiogenic factors, specifically VEGF and and the soluble VEGF receptor fms-like tyrosine kinase-1 (sFlt-l), are directly influenced by hypoxia in placental ischemia. While adenosine has been reported to be an important regulator of VEGF in vascular tissue, the importance of adenosine in regulating VEGF and sFlt-1 in placental tissue is unclear. Here, we have investigated the role of adenosine in the secretion of VEGF and the antiangiogenic protein sFlt-1 in placental villous explants. Under normoxic conditions (6% oxygen), the nonspecific adenosine receptor antagonist, 8-sulphophenyltheophylline (8-SPT) had no effect on either VEGF (P = 0.38) or sFlt-1 (P = 0.56) secretion. However, under hypoxic conditions (1% oxygen), 8-SPT attenuated the increase in the secretion of both VEGF and sFlt-1 (P < 0.05 and P < 0.005, respectively). Exogenous and the adenosine transporter inhibitor dipyridamole (which increases extra-cellular levels of adenosine) showed differential effects under normoxic conditions: sFlt-1 levels in media increased significantly (P < 0.05), whereas VEGF was unaffected (P = 0.67 and P = 0.19, respectively). These data indicate that extracellular adenosine can regulate VEGF and sFlt-1 secretion in the hypoxic placenta and could, therefore, control the balance of these competing angiogenic factors in diseases characterized by placental ischemia. placental ischemia; soluble vascular endothelial growth factor rl; preeclampsia; reduced uterine perfusion pressure doi: 10.1152/ajpregu.00330.2010

Placenta ischemia, the initiating event in preeclampsia (PE), is associated with fetal growth restriction. Inhibition of the agonistic autoantibody against the angiotensin type 1 receptor AT1-AA, using an epitope-binding inhibitory peptide ('n7AAc') attenuates increased blood pressure at gestational day (G)19 in the clinically relevant reduced uterine perfusion pressure (RUPP) model of PE. Thus we tested the hypothesis that maternal administration of 'n7AAc' does not transfer to the fetus, improves uterine blood flow and fetal growth, and attenuates elevated placental expression of miRNAs implicated in PE and FGR. Sham or RUPP surgery was performed at G14 with vehicle or 'n7AAc' (144 mg/day) administered via an osmotic pump from G14 to G20. Maternal plasma levels of the peptide on G20 were 16.28 ± 4.4 nM, and fetal plasma levels were significantly lower at 1.15 ± 1.7 nM (P = 0.0007). The uterine artery resistance index was significantly elevated in RUPP (P < 0.0001) but was not increased in 'n7AAc'-RUPP or 'n7AAc'-Sham versus Sham. A significant reduction in fetal weight at G20 in RUPP (P = 0.003) was not observed in 'n7AAc'-RUPP. Yet, percent survival was reduced in RUPP (P = 0.0007) and 'n7AAc'-RUPP (P < 0.0002). Correlation analysis indicated the reduction in percent survival during gestation was specific to the RUPP (r = 0.5342, P = 0.043) and independent of 'n7AAc'. Placental miR-155 (P = 0.0091) and miR-181a (P = 0.0384) expression was upregulated in RUPP at G20 but was not elevated in 'n7AAc'-RUPP. Collectively, our results suggest that maternal administration of 'n7AAc' does not alter fetal growth in the RUPP implicating its potential as a therapeutic for the treatment of PE. NEW & NOTEWORTHY The seven amino acid inhibitory peptide to the AT1-AA ('n7AAc') has limited transfer to the fetus at gestational day 20, improves uterine blood flow and fetal growth in the reduced uterine perfusion pressure model of preeclampsia (PE), and does not impair fetal survival during gestation in sham-operated or placental ischemic rats. Collectively, these findings suggest that maternal administration of 'n7AAc' as an effective strategy for the treatment of PE is associated with improved outcomes in the fetus. [ABSTRACT FROM AUTHOR]

TNF-[alpha] enhances contraction and inhibits endothelial NO-cGMP relaxation in systemic vessels of pregnant rats. Am J Physiol Regulatory Integrative Comp Physiol 283: R130-R143, 2002. First published February 28, 2002; 10.1152/ajpregu.00704. 2001.--Tumor necrosis factor-[alpha] (TNF-[alpha]) is elevated in the plasma of preeclamptic women and may have a role in pregnancy-induced hypertension. However, whether the hemodynamic effects of TNF-[alpha] reflect the direct effects on vascular reactivity is unclear. We tested the hypothesis that TNF-[alpha] impairs endothelium-dependent relaxation and enhances vascular contraction in systemic vessels of pregnant rats. We measured isometric contraction in aortic strips isolated from virgin and pregnant Sprague-Dawley rats (nontreated vs. treated for 2 h with 10-1,000 pg/ml TNF-[alpha]). In endothelium-intact vascular strips, TNF-[alpha] caused greater enhancement of phenylephrine (Phe) contraction in pregnant than virgin rats. TNF-[alpha] caused significant inhibition of ACh- and bradykinin-induced vascular relaxation and nitrite/nitrate production that were more prominent in pregnant than virgin rats. [N.sup.G]-nitro-L-arginine methyl ester [L-NAME, 100 [micro]M, an inhibitor of nitric oxide (NO) synthase] or 1H-[1,2,4]oxadiazolo[4,3]-quinoxalin-1-one (ODQ, 1 [micro]M, an inhibitor of cGMP production in smooth muscle) inhibited ACh relaxation and enhanced Phe contraction in nontreated but to a lesser extent in TNF-[alpha]-treated vessels, particularly those of pregnant rats. Endothelium removal enhanced Phe contraction in nontreated but not TNF-[alpha]-treated vessels, especially those of pregnant rats. Relaxation of Phe contraction with the NO donor sodium nitroprusside was not different between nontreated and TNF-[alpha]-treated vessels. Thus TNF-[alpha] enhances vascular contraction and inhibits endothelium-dependent NO-cGMP-mediated vascular relaxation in systemic vessels, particularly those of pregnant rats. The results support a direct role for TNF-[alpha] as a possible mediator of increased vascular resistance associated with pregnancy-induced hypertension. cytokines; endothelium; nitric oxide; pregnancy; arterial pressure; tumor necrosis factor-[alpha]

Rabbits subjected to a regimen of high-cholesterol diet were analyzed to determine the effects of cholesterol feeding on electrolyte excretion and renal hemodynamics. High-cholesterol diets in rabbits induced hypercholesterolemia and large-vessel atherosclerotic lesions. Cholesterol feeding also increased plasma cholesterol levels without altering renal microvascular architecture and resting renal hemodynamic function.

The cardiovascular consequences of obesity were investigated in a model using rabbits with dietary-induced obesity. Obese rabbits were 46% heavier and had a higher resting heart rate than lean rabbits after 12 wks. of high-fat diet. They also developed hypertension, hyperinsulinemia, hyperglycemia and cardiac hypertrophy. They also showed a significant increase in triglycerides and left ventricle protein.

Enhanced renal expression of preproendothelin mRNA during chronic angiotensin II hypertension. Am J Physiol Regulatory Integrative Comp Physiol 280: R1388-R1392, 2001.--The purpose of this study was to determine the role of endothelin in mediating the renal hemodynamic and arterial pressure changes observed during chronic ANG II-induced hypertension. ANG II (50 ng [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]) was chronically infused into the jugular vein by miniosmotic pump for 2 wk in male Sprague-Dawley rats with and without endothelin type A ([ET.sub.A])-receptor antagonist ABT-627 (5 mg [multiplied by] [kg.sup.-1] [multiplied by] [day.sup.-1]) pretreatment. Arterial pressure increased in ANG II rats compared with control rats (149 [+ or -] 5 vs. 121 [+ or -] 6 mmHg, P [is less than] 0.05, respectively). Renal expression of preproendothelin mRNA was increased by ~50% in both the medulla and cortex of ANG II rats. The hypertensive effect of ANG II was completely abolished in rats pretreated with the [ET.sub.A]-receptor antagonist (114 [+ or -] 5 mmHg, P [is less than] 0.05). Glomerular filtration rate was decreased by 33% in ANG II rats, and this response was attenuated in rats pretreated with [ET.sub.A]-receptor antagonist. These data indicate that activation of the renal endothelin system by ANG II may play an important role in mediating chronic renal and hypertensive actions of ANG II. glomerular filtration rate; mean arterial pressure; renal preproendothelin

[[[Ca.sup.2+]].sub.i] signaling in renal arterial smooth muscle cells of pregnant rat is enhanced during inhibition of NOS. Am J Physiol Regulatory Integrative Comp Physiol 280: R87-R99, 2001.-- Vascular resistance and arterial pressure are reduced during normal pregnancy, but dangerously elevated during pregnancy-induced hypertension (PIH), and changes in nitric oxide (NO) synthesis have been hypothesized as one potential cause. In support of this hypothesis, chronic inhibition of NO synthesis in pregnant rats has been shown to cause significant increases in renal vascular resistance and hypertension; however, the cellular mechanisms involved are unclear. We tested the hypothesis that the pregnancy-associated changes in renal vascular resistance reflect changes in contractility and intracellular [Ca.sup.2+] concentration ([[[Ca.sup.2+]].sub.i]) of renal arterial smooth muscle. Smooth muscle cells were isolated from renal interlobular arteries of virgin and pregnant Sprague-Dawley rats untreated or treated with the NO synthase inhibitor nitro-L-arginine methyl ester (L-NAME; 4 mg [multiplied by] [kg.sup.-1] [multiplied by] [day.sup.-1] for 5 days), then loaded with fura 2. In cells of virgin rats incubated in Hanks' solution (1 mM [Ca.sup.2+]), the basal [[[Ca.sup.2+]].sub.i] was 86 [+ or -] 6 nM. Phenylephrine (Phe, [10.sup.-5] M) caused a transient increase in [[[Ca.sup.2+]].sub.i] to 417 [+ or -] 11 nM and maintained an increase to 183 [+ or -] 8 nM and 32 [+ or -] 3% cell contraction. Membrane depolarization by 51 mM KCl, which stimulates [Ca.sup.2+] entry from the extracellular space, caused maintained increase in [[[Ca.sup.2+]].sub.i] to 292 [+ or -] 12 nM and 31 [+ or -] 2% contraction. The maintained Phe- and KCl-induced [[[Ca.sup.2+]].sub.i] and contractions were reduced in pregnant rats but significantly enhanced in pregnant rats treated with L-NAME. Phe-and KCl-induced contraction and [[[Ca.sup.2+]].sub.i] were not significantly different between untreated and L-NAME-treated virgin rats or between untreated and L-NAME + L-arginine treated pregnant rats. In [Ca.sup.2+]-free Hanks', application of Phe or caffeine (10 mM), to stimulate [Ca.sup.2+] release from the intracellular stores, caused a transient increase in [[[Ca.sup.2+]].sub.i] and a small cell contraction that were not significantly different among the different groups. Thus renal interlobular smooth muscle of normal pregnant rats exhibits reduction in [[[Ca.sup.2+]].sub.i] signaling that involves [Ca.sup.2+] entry from the extracellular space but not [Ca.sup.2+] release from the intracellular stores. The reduced renal smooth muscle cell contraction and [[[Ca.sup.2+]].sub.i] in pregnant rats may explain the decreased renal vascular resistance associated with normal pregnancy, whereas the enhanced cell contraction and [[[Ca.sup.2+]].sub.i] during inhibition of NO synthesis in pregnant rats may, in part, explain the increased renal vascular resistance associated with PIH. vascular resistance; hypertension; calcium; contraction

Kanashiro, Celia A., Kathy L. Cockrell, Barbara T. Alexander, Joey P. Granger, and Raouf A. Khalil. Pregnancy-associated reduction in vascular protein kinase C activity rebounds during inhibition of NO synthesis. Am. J. Physiol. Regulatory Integrative Comp. Physiol. 278: R295-R303, 2000.--Vascular reactivity has been shown to be reduced during pregnancy and to be enhanced during chronic inhibition of nitric oxide (NO) synthesis in pregnant rats; however, the cellular mechanisms involved are unclear. The purpose of this study was to investigate whether the pregnancy-induced changes in vascular reactivity are associated with changes in the amount and/or activity of vascular protein kinase C (PKC). Active stress as well as the amount and activity of PKC was measured in deendothelialized thoracic aortic strips from virgin and pregnant rats untreated or treated with the NO synthase inhibitor [N.sup.G]-nitro-L-arginine methyl ester (L-NAME). In virgin rats, the PKC activator phorbol 12,13-dibutyrate (PDBu, [10.sup.-6] M) and the a-adrenergic agonist phenylephrine (Phe, [10.sup.-5] M) caused significant increases in active stress and PKC activity that were inhibited by the PKC inhibitors staurosporine and calphostin C. Western blot analysis in aortic strips of virgin rats showed significant amount of the [Alpha]-PKC isoform. Both PDBu and Phe caused significant translocation of [Alpha]-PKC from the cytosolic to the particulate fraction. Compared with virgin rats, the PDBu- and Phe-stimulated active stress and PKC activity as well as the amount and the PDBu- and Phe-induced translocation of [Alpha]-PKC were significantly reduced in late pregnant rats but significantly enhanced in pregnant rats treated with L-NAME. The PDBu- and Pheinduced changes in active stress and the amount, distribution, and activity of [Alpha]-PKC in virgin rats treated with L-NAME were not significantly different from that in virgin rats, whereas the changes in pregnant rats treated with L-NAME + the NO synthase substrate L-arginine were not significantly different from that in pregnant rats. These results provide evidence that a PKC-mediated contractile pathway in vascular smooth muscle is reduced during pregnancy and significantly enhanced during chronic inhibition of NO synthesis. The results suggest that one possible mechanism of the pregnancy-associated changes in vascular reactivity may involve changes in the amount and activity of the [Alpha]-PKC isoform. nitric oxide; vascular smooth muscle; hypertension