Vasorelaxation In Uterine Arteries Research Articles

H2S donor GYY4137 mitigates sFlt-1-induced hypertension and vascular dysfunction in pregnant rats

Abstract Gestational hypertension, often associated with elevated soluble Fms-related receptor tyrosine kinase 1 (sFlt-1), poses significant risks to both maternal and fetal health. Hydrogen sulfide (H2S), a gasotransmitter, has demonstrated blood pressure-lowering effects in hypertensive animals and humans. However, its role in pregnancy-induced hypertension remains unclear. This study investigated the impact of GYY4137, a slow-release H2S donor, on sFlt-1-induced hypertension in pregnant rats . Pregnant rats were administered sFlt-1 (6 μg/kg/day, intravenously) or vehicle from gestation day (GD) 12–20. A subset of these groups received GYY4137 ( 50 mg/kg/day, intraperitoneal) from GD 16–20. Serum H2S levels, mean arterial blood pressure, uterine artery blood flow, and vascular reactivity were assessed. Elevated sFlt-1 reduced both maternal weight gain and serum H2S levels. GYY4137 treatment restored both weight gain and H2S levels in sFlt-1 dams. sFlt-1 increased mean arterial pressure and decreased uterine artery blood flow in pregnant rats. However, treatment with GYY4137 normalized blood pressure and restored uterine blood flow in sFlt-1 dams. sFlt-1 dams exhibited heightened vasoconstriction to phenylephrine and GYY4137 significantly mitigated the exaggerated vascular contraction. Notably, sFlt-1 impaired endothelium-dependent relaxation, while GYY4137 attenuated this impairment by upregulating eNOS protein levels and enhancing vasorelaxation in uterine arteries. GYY4137 mitigated sFlt-1-induced fetal growth restriction. In conclusion, sFlt-1 mediated hypertension is associated with decreased H2S levels. Replenishing H2S with the donor GYY4137 mitigates hypertension and improves vascular function and fetal growth outcomes. This suggests modulation of H2S could offer a novel therapeutic strategy for managing gestational hypertension and adverse fetal effects.

Restoring Angiotensin Type 2 Receptor Function Reverses PFOS-Induced Vascular Hyper-Reactivity and Hypertension in Pregnancy.

Perfluorooctane sulfonic acid (PFOS) exposure during pregnancy induces hypertension with decreased vasodilatory angiotensin type-2 receptor (AT2R) expression and impaired vascular reactivity and fetal weights. We hypothesized that AT2R activation restores the AT1R/AT2R balance and reverses gestational hypertension by improving vascular mechanisms. Pregnant Sprague-Dawley rats were exposed to PFOS through drinking water (50 μg/mL) from gestation day (GD) 4-20. Controls received drinking water with no detectable PFOS. Control and PFOS-exposed rats were treated with AT2R agonist Compound 21 (C21; 0.3 mg/kg/day, SC) from GD 15-20. In PFOS dams, blood pressure was higher, blood flow in the uterine artery was reduced, and C21 reversed these to control levels. C21 mitigated the heightened contraction response to Ang II and enhanced endothelium-dependent vasorelaxation in uterine arteries of PFOS dams. The observed vascular effects of C21 were correlated with reduced AT1R levels and increased AT2R and eNOS protein levels. C21 also increased plasma bradykinin production in PFOS dams and attenuated the fetoplacental growth restriction. These data suggest that C21 improves the PFOS-induced maternal vascular dysfunction and blood flow to the fetoplacental unit, providing preclinical evidence to support that AT2R activation may be an important target for preventing or treating PFOS-induced adverse maternal and fetal outcomes.

Activation of angiotensin type 2 receptor attenuates testosterone-induced hypertension and uterine vascular resistance in pregnant rats†.

Preeclampsia is a pregnancy-related hypertensive disorder with unclear mechanisms. While hypersensitivity to angiotensin II via vasoconstrictive angiotensin type-1 receptor (AT1R) is observed in preeclampsia, the importance of vasodilatory angiotensin type-2 receptor (AT2R) in the control of vascular dysfunction is less clear. We assessed whether AT1R, AT2R, and endothelial nitric oxide synthase (eNOS) expression are altered in placental vessels of preeclamptic women and tested if ex vivo incubation with AT2R agonist Compound 21 (C21; 1μM) could restore AT1R, AT2R, and eNOS balance. Further, using a rat model of gestational hypertension induced by elevated testosterone, we examined whether C21 (1μg/kg/day, oral) could preserve AT1R and AT2R balance and improve blood pressure, uterine artery blood flow, and vascular function. Western blots revealed that AT1R protein level was higher while AT2R and eNOS protein were reduced in preeclamptic placental vessels, and AT2R agonist C21 decreased AT1R and increased AT2R and eNOS protein levels in preeclamptic vessels. In testosterone dams, blood pressure was higher, and uterine artery blood flow was reduced, and C21 treatment reversed these levels similar to those in controls dams. C21 attenuated the exaggerated Ang II contraction and improved endothelium-dependent vasorelaxation in uterine arteries of testosterone dams. These C21-mediated vascular effects were associated with decreased AT1R and increased AT2R and eNOS protein levels. C21 also increased serum nitrate/nitrite and bradykinin production in testosterone dams and attenuated the fetoplacental growth restriction. Thus, AT1R upregulation and AT2R downregulation are observed in preeclampsia and testosterone model, and increasing AT2R activity could help restore AT1R and AT2R balance and improve gestational vascular function.

Luteolin-induced vasorelaxation in uterine arteries from normal pregnant rats.

The flavonoid, luteolin, promotes vasorelaxation in various arteries through endothelial-dependent and independent mechanisms. Although there is growing interest in the vasoactive effects of flavonoids on maternal vascular function during pregnancy, it is unknown whether luteolin elicits vasorelaxation in the uterine circulation. We tested the hypothesis that luteolin induces vasorelaxation via endothelial-dependent mechanisms in uterine arteries from normal pregnant rats during late gestation. Uterine arteries and aortas were isolated from Sprague-Dawley rats at gestational day 19 and prepared for wire myography. The potency of luteolin-induced vasorelaxation was examined between uterine arteries and the aortas. By 50µM of luteolin, there was complete relaxation (100.5±5.2%) in uterine arteries as compared to aortas (27.5±10.0%). Even the highest concentration of 100µM luteolin produced less than half relaxation (43.6±8.6%) in aortas compared to uterine arteries. We then explored if luteolin-induced vasorelaxation in uterine arteries from pregnant rats was mediated by endothelial-dependent vasorelaxation pathways, including nitric oxide synthase (NOS), cyclooxygenase (COX), or potassium (K+) channels. Blocking these pathways with N(G)-Nitro-l-arginine methyl ester hydrochloride (L-NAME), indomethacin, or tetraethylammonium (TEA)/high potassium chloride (KCl), respectively, did not alter luteolin responses in uterine arteries from pregnant rats. These findings suggested that endothelial factors may not mediate luteolin-induced vasorelaxation in uterine arteries during pregnancy. Indeed, experiments where the endothelium was removed did not alter luteolin-induced vasorelaxation in uterine arteries during pregnancy. Luteolin directly promotes vasorelaxation in the medial smooth muscle layer of uterine arteries during normal pregnancy.

Peroxisome proliferator-activated receptor gamma blunts endothelin-1-mediated contraction of the uterine artery in a murine model of high-altitude pregnancy.

The environmental hypoxia of high altitude (HA) increases the incidence of intrauterine growth restriction (IUGR) approximately threefold. The peroxisome proliferator-activated receptor γ (PPAR-γ), a ligand-activated nuclear receptor that promotes vasorelaxation by increasing nitric oxide and downregulating endothelin-1 (ET-1) production, has been implicated in IUGR. Based on our prior work indicating that pharmacologic activation of the PPARγ pathway protects against hypoxia-associated IUGR, we used an experimental murine model to determine whether such effects may be attributed to vasodilatory effects in the uteroplacental circulation. Using wire myography, ex vivo vasoreactivity studies were conducted in uterine arteries (UtA) isolated from pregnant mice exposed to hypoxia or normoxia from gestational day 14.5 to 18.5. Exposure to troglitazone, a high-affinity PPARγ agonist-induced vasorelaxation in UtA preconstricted with phenylephrine, with HA-UtA showing increased sensitivity. Troglitazone blunted ET-1-induced contraction of UtA in hypoxic and normoxic dams equivalently. Immunohistological analysis revealed enhanced staining for ET-1 receptors in the placental labyrinthine zone in hypoxic compared to normoxic dams. Our results suggest that pharmacologic PPAR-γ activation, via its vasoactive properties, may protect the fetal growth under hypoxic conditions by improving uteroplacental perfusion and thereby justify further investigation into PPARγ as a therapeutic target for IUGR in pregnancies complicated by hypoxia.