Prenatal Testosterone Exposure Induces Hypertension in Adult Females via Androgen Receptor–Dependent Protein Kinase Cδ–Mediated Mechanism

Selvanesan, Blesson Chellakkan; Chinnathambi, Vijayakumar; Hankins, Gary D.V.; Yallampalli, Chandra; Sathishkumar, K.

doi:10.1161/hypertensionaha.114.04521

Cited by 37 publications

(34 citation statements)

References 61 publications

(59 reference statements)

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“…T 0 induced blood vessel damage and subsequent hypertension through a PKCδ (activation of protein kinase C δ)-dependent pathway and increased vascular responses to vasoconstrictor agents, such as arachidonic acid and norepinephrine in rats. 37,38 However, estrogens have been reported to be potent vasodilators that lead to an increase in blood flow in selected organs, with the greatest response in the uterus. 39 During mammalian pregnancy, adequate blood supply to the uterine-placental region is crucial to meeting the growing requirement of the fetus.…”

Section: Discussionmentioning

confidence: 99%

“…The relative density of each specific molecule was measured by 36 densitometry, and its value was compared with the GAPDH or -actin value from the same blot. 37 Immunohistochemistry 38 The tissues were fixed in 4% paraformaldehyde (PFA), gradually dehydrated in ethanol and 39 embedded in paraffin wax. The 5-μm-thick paraffin sections were subjected to routine 40 rehydration and antigen retrieval before being incubated with the appropriate antibody.…”

Section: Sources Of Fundingmentioning

confidence: 99%

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Testosterone Represses Estrogen Signaling by Upregulating miR-22

Shao

Liu

et al. 2017

Hypertension

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P reeclampsia (PE), affecting ≈5% to 7% of pregnancies worldwide, is a multisystem syndrome that occurs during the third trimester of human pregnancy, and it is a leading cause of maternal and perinatal morbidity and mortality. [1][2][3][4] Placental deficiencies are widely recognized as the principal pathological origin of the disorder.Preeclamptic patients usually present with high circulating testosterone and reduced estradiol production during gestation, and therefore, they are considered to experience endocrine disorders. [5][6][7][8] Physiologically, the circulating testosterone and estradiol levels in pregnant women increase from the first trimester and are further elevated toward the end of pregnancy. 9 The placenta is an important source of steroid hormone production throughout gestation, although the ovarian luteal cells have that role in early pregnancy. The placenta can manufacture pregnenolone and express several enzymes that are fundamentally required for the biosynthetic conversion of cholesterol to androgens and estrogens, such as CYP17 (17α-hydroxy/17,20-lyase), 3β-HSD (3β-hydroxysteroid dehydrogenase), 17β-HSD, and aromatase. Specifically, the placental aromatase acts to convert androstenedione (A 4 ) into estrone (E 1 ), and testosterone (T 0 ) into 17β-estradiol (E 2 ), and 17β-HSD3 works to convert A 4 into T 0 .9 The aberrantly increased testosterone level and decreased estradiol Abstract-Preeclampsia, a multisystem syndrome occurring during mid-to late gestation in humans, is a leading cause of maternal and perinatal morbidity and mortality. Patients usually present with high circulating testosterone and reduced estradiol production, but the mechanisms remain unclear. Revealing the mechanism that modulating the imbalance of testosterone and estradiol in preeclampsia is of great value in understanding the cause of the disease. The placenta is the predominant source of steroid hormone production during gestation, and we observed markedly increased 17β-HSD3 (17β-hydroxysteroid dehydrogenase 3) levels and downregulated aromatase expression, the key enzymes responsible for synthesis of testosterone and estradiol, respectively, in preeclamptic placentas compared with controls. Furthermore, we found a significant upregulation of microRNA (miR)-22 in preeclamptic placentas. In a trophoblast cell line, JEG-3 cells, testosterone repressed the expression of aromatase and estrogen receptor α and the production of estradiol while promoting miR-22 expression. miR-22 directly targeted and inhibited estrogen receptor α expression while indirectly decreasing aromatase expression and estradiol production by interfering with estrogen receptor α signaling. Furthermore, inhibition of miR-22 expression significantly reversed the inhibitory effect of testosterone on de novo estradiol synthesis in human trophoblastic cells. The findings reveal a mechanism underlying the balanced production of androgen and estrogen modulated by miR-22 in the human placenta and provide new insights into the pathogenesis of preeclam...

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Section: Discussionmentioning

confidence: 99%

Section: Sources Of Fundingmentioning

confidence: 99%

Testosterone Represses Estrogen Signaling by Upregulating miR-22

Shao

Liu

et al. 2017

Hypertension

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“…85–23, revised 1996). As we described earlier, 31;43;46;47 timed pregnant Sprague-Dawley rats (gestational day [GD] 12; presence of copulation plug is day 1), purchased from Charles River (Wilmington, MA), were used in this study. After acclimatization, on GD 14, dams were randomly divided into 2 groups.…”

Section: Methodsmentioning

confidence: 99%

Elevated Testosterone Reduces Uterine Blood Flow, Spiral Artery Elongation, and Placental Oxygenation in Pregnant Rats

et al. 2016

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Elevated maternal testosterone levels are shown to cause fetal growth restriction, eventually culminating in sex-specific adult-onset hypertension that is more pronounced in males than females. In this study, we tested whether utero- and feto-placental disturbances underlie fetal growth restriction and if these changes vary in male and female placentas. Pregnant Sprague-Dawley rats were injected with vehicle (n=16) or testosterone propionate (0.5 mg/Kg/day from gestation day 15–19; n=16). On gestation day 20, we quantified uterine artery blood flow using microultrasound, visualized placental arterial network using x-ray microcomputed tomography, determined fetoplacental hypoxia using pimonidazole and hypoxia-inducible factor-1α, and used Affymetrix array to determine changes in placental expression of genes involved in vascular development. Plasma testosterone levels increased 2-fold in testosterone-injected rats. Placental and fetal weights were lower in rats with elevated testosterone. Uterine artery blood flow was lower and resistance index was higher in testosterone group. Radial and spiral artery diameter and length, number of fetoplacental arterial branches, and umbilical artery diameter were reduced in the testosterone group. In addition, markers of hypoxia in the placentas and fetuses were elevated in the testosterone group. The magnitude of changes in placental vasculature and hypoxia were greater in males than females and were associated with sex-specific alteration of unique sets of genes involved in angiogenesis and blood vessel morphogenesis. The results demonstrate that elevated testosterone during gestation induces a decrease in uterine arterial blood flow and fetal sex-related uteroplacental vascular changes, which may set the stage for subsequent sex differences in adult-onset diseases.

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“…Blesson and colleagues recently reported that prenatal testosterone excess programs an increase in blood pressure associated with an elevation in testosterone in female offspring mimicking the pathogenesis of polycystic ovary syndrome ( PCOS ) (43). This study published in Hypertension demonstrated that chronic blockade of the androgen receptor with flutamide abolished the programmed increase in blood pressure in the prenatal testosterone exposed female offspring (43) implicating an important role for hyperandrogenism in the pathogenesis of hypertension in this model (43). It is well established that protein kinase C ( PKC ) isoforms modulate vascular activity.…”

Section: Sex Steroids the Renin Angiotensin System And The Developmmentioning

confidence: 99%