Enhanced Mesenteric Arterial Responsiveness to Angiotensin II Is Androgen Receptor-Dependent in Prenatally Protein-Restricted Adult Female Rat Offspring1

Abstract

Gestational protein restriction results in intrauterine growth restriction and hypertension in adult female growth-restricted rats. Enhanced vascular responsiveness to angiotensin II is observed, and blockade of the renin-angiotensin system abolishes hypertension in adult growth-restricted rats, suggesting that the renin-angiotensin system contributes to intrauterine growth restriction-induced hypertension. Moreover, growthrestricted adult rats have higher plasma testosterone levels, and antiandrogen treatment abolishes hypertension, indicating an important role for testosterone. We hypothesized that androgens may play a pivotal role in the enhanced responsiveness to Ang II and hypertension. Female offspring of pregnant rats fed 20% protein (control) or 6% protein diet (protein restricted), at 6 mo of age, were studied. Plasma testosterone and mean arterial pressure in protein-restricted offspring were significantly higher compared to controls. Flutamide treatment (10 mg/kg/day subcutaneously for 10 days) reduced mean arterial pressure in protein-restricted offspring but was without significant effect in controls. Vascular Agtr1/Agtr2 ratio was significantly higher in protein-restricted offspring, an effect that was reversed by flutamide. Flutamide treatment did not have any effect on Agtr1/Agtr2 ratio in controls. Enhanced contractile response to angiotensin II in mesenteric arteries was observed in protein-restricted offspring compared with control. Flutamide treatment reversed the enhanced contractile response to angiotensin II in protein-restricted offspring without significant effect in controls. Vascular reactivity to phenylephrine was similar between the control and protein-restricted offspring with and without flutamide treatment, suggesting that enhanced contractile response and flutamide's reversal effect is specific to angiotensin II. These results suggest that prenatally proteinrestricted rats exhibit an enhanced responsiveness to angiotensin II that is testosterone-dependent.

The effect of intrauterine growth restriction on Ca2+-activated force and contractile protein expression in the mesenteric artery of adult (6-month-old) male and female Wistar-Kyoto rats

“…Sathishkumar et al. () discovered an enhanced response to Angiotensin II (potent vasoconstrictor) in the mesenteric artery of 6‐month‐old females following a maternal protein restriction diet, however, these same arteries had no change in sensitivity to PE. Others have also shown an age‐specific difference (Hemmings et al.…”

The Programming Power of the Placenta

“…Numerous adverse prenatal environments alter postnatal growth, but the specific effect is dependent on the timing and severity of the insult, as well as on the quality of the postnatal environment to which the offspring is exposed. Prenatal perturbations, such as calorie restriction (10–35%; Kind et al, 1999 , 2002 , 2003 ; Vickers et al, 2000 ; Riviere et al, 2005 ; Breton et al, 2009 ; Camm et al, 2011 ; Lukaszewski et al, 2011 , 2013 ), low-protein diet (6%; Sathishkumar et al, 2009 , 2012 , 2015 ), iron restriction (Crowe et al, 1995 ; Lewis et al, 2001c , 2002 ) and uterine artery ligation (e.g., Wlodek et al, 2007 , 2008 ; Siebel et al, 2008 ) in rats and guinea pigs reduce birth weight. Furthermore, offspring remain smaller through to adulthood, irrespective of the stage at which the manipulation occurs prenatally.…”

In Utero Origins of Hypertension: Mechanisms and Targets for Therapy

“…In a model of maternal nutrient restriction in sheep, female adult offspring (6 yr of age) were demonstrated to have reduced steroidogenic enzyme expression and subsequently reduced circulating and luteal progesterone levels (228). In the female offspring of protein-restricted rats, plasma testosterone levels were increased along with increased blood pressure (359). In this study, treatment of the offspring with the androgen receptor antagonist flutamide (10 mg·kg Ϫ1 ·day Ϫ1 sc, for 10 days) ameliorated the hypertensive phenotype and reversed the enhanced mesenteric artery responses to ANG II, suggesting that the alterations in RAS might be androgen-dependent.…”