title: Gestational exposure to elevated testosterone levels induces hypertension via heightened vascular angiotensin II type 1 receptor signaling in rats.
abstract: Pre-eclampsia is a life-threatening pregnancy disorder whose pathogenesis remains unclear. Plasma testosterone levels are elevated in pregnant women with pre-eclampsia and polycystic ovary syndrome, who often develop gestational hypertension. We tested the hypothesis that increased gestational testosterone levels induce hypertension via heightened angiotensin II signaling. Pregnant Sprague-Dawley rats were injected with vehicle or testosterone propionate from Gestational Day 15 to 19 to induce a 2-fold increase in plasma testosterone levels, similar to levels observed in clinical conditions like pre-eclampsia. A subset of rats in these two groups was given losartan, an angiotensin II type 1 receptor antagonist by gavage during the course of testosterone exposure. Blood pressure levels were assessed through a carotid arterial catheter and endothelium-independent vascular reactivity through wire myography. Angiotensin II levels in plasma and angiotensin II type 1 receptor expression in mesenteric arteries were also examined. Blood pressure levels were significantly higher on Gestational Day 20 in testosterone-treated dams than in controls. Treatment with losartan during the course of testosterone exposure significantly attenuated testosterone-induced hypertension. Plasma angiotensin II levels were not significantly different between control and testosterone-treated rats; however, elevated testosterone levels significantly increased angiotensin II type 1 receptor protein levels in the mesenteric arteries. In testosterone-treated rats, mesenteric artery contractile responses to angiotensin II were significantly greater, whereas contractile responses to K(+) depolarization and phenylephrine were unaffected. The results demonstrate that elevated testosterone during gestation induces hypertension in pregnant rats via heightened angiotensin II type 1 receptor-mediated signaling, providing a molecular mechanism linking elevated maternal testosterone levels with gestational hypertension.
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Vijayakumar
authors.initials: V
authors.lastname: Chinnathambi
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Amar S
authors.initials: AS
authors.lastname: More
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas.
authors.forename: Gary D
authors.initials: GD
authors.lastname: Hankins
authors.affiliation: Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.
authors.forename: Chandra
authors.initials: C
authors.lastname: Yallampalli
authors.affiliation: Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas kusathis@utmb.edu.
authors.forename: Kunju
authors.initials: K
authors.lastname: Sathishkumar
mesh_terms: D000804:Angiotensin II / Q000097:blood; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D004195:Disease Models, Animal; D005260:Female; D046110:Hypertension, Pregnancy-Induced / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D019808:Losartan / Q000494:pharmacology / Q000627:therapeutic use*; D008638:Mesenteric Arteries / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D013739:Testosterone / Q000097:blood / Q000494:pharmacology*
chemical_list: D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D013739:Testosterone; D019808:Losartan
keywords: AGTR1; angiotensin; blood pressure; losartan; mesenteric arteries; pre-eclampsia; pregnancy; testosterone; vascular function