Maternal Angiotensin II–Induced Hypertension Sensitizes Postweaning High‐Fat Diet–Elicited Hypertensive Response Through Increased Brain Reactivity in Rat Offspring

Abstract

Background Prenatal and postnatal insults can induce a physiological state that leaves offspring later in life vulnerable to subsequent challenges (stressors) eliciting cardiometabolic diseases including hypertension. In this study, we investigated whether maternal angiotensin II–induced hypertension in rats sensitizes postweaning high‐fat diet (HFD)‐elicited hypertensive response and whether this is associated with autonomic dysfunction and altered central mechanisms controlling sympathetic tone in offspring. Methods and Results When eating a low‐lard‐fat diet, basal mean arterial pressure of male offspring of normotensive or hypertensive dams were comparable. However, HFD feeding significantly increased mean arterial pressure in offspring of normotensive and hypertensive dams, but the elevated mean arterial pressure induced by HFD was greater in offspring of hypertensive dams, which was accompanied by greater sympathetic tone and enhanced pressor responses to centrally administrated angiotensin II or leptin. HFD feeding also produced comparable elevations in cardiac sympathetic activity and plasma levels of angiotensin II, interleukin‐6, and leptin in offspring of normotensive and hypertensive dams. Reverse transcriptase polymerase chain reaction analyses in key forebrain regions implicated in the control of sympathetic tone and blood pressure indicated that HFD feeding led to greater increases in mRNA expression of leptin, several components of the renin‐angiotensin system and proinflammatory cytokines in offspring of hypertensive dams when compared with offspring of normotensive dams. Conclusions The results indicate that maternal hypertension sensitized male adult offspring to HFD‐induced hypertension. Increased expression of renin‐angiotensin system components and proinflammatory cytokines, elevated brain reactivity to pressor stimuli, and augmented sympathetic drive to the cardiovascular system likely contributed.

Loss of the Protective Effect of Estrogen Contributes to Maternal Gestational Hypertension‐Induced Hypertensive Response Sensitization Elicited by Postweaning High‐Fat Diet in Female Offspring

“…In our previous study, male offspring were studied under identical experimental conditions to those described for the female offspring in the current study. 30 For the sake of comparison, the data from the previous report in males are compared with females in Table 3 . When compared with the male HFD fed offspring of either normotensive dams (120.3±1.3 mm Hg) or hypertensive dams (128.7±1.6 mm Hg), intact female offspring had a relatively smaller increase in MAP ( P <0.05), indicating sex differences in MHT‐induced HTRS elicited by postweaning HFD (Table 3 ).…”

“… The male MAP and HR data presented in this table were collected under exactly the same conditions as the female data. The male data were published previously 30 and are presented herein to facilitate comparison with results obtained in females. P <0.05 is significant.…”

“… 43 In the current study, we studied relatively young female offspring fed with HFD (15–16 weeks of age versus 12 months in other studies) and did not find elevated sympathetic activity in intact female offspring or an enhanced pressor response to central leptin in intact and ovariectomized offspring. This suggests that leptin may not be involved in postweaning HFD‐induced change in BP in female offspring, but did in the male offspring, 30 even though there were changes in plasma levels and brain mRNA expression of leptin in HFD fed female offspring before and after ovariectomy. On the basis of aforementioned studies and current results, it is likely that the actions of leptin in obesity‐related hypertension in females exposed to prenatal insults may depend on the animal model studied, age, species, and whether the females are in prereproductive or postreproductive senescence.…”

“…All offspring were weaned at 3 weeks of age, and feeding began with one half of the animals receiving a low‐lard‐fat diet (LFD; 10% calories from lard; 3.85 kcal/g; D12450J; Research Diets Inc) and the other one‐half receiving a HFD (60% calories from lard; 5.24 kcal/g; D12492; Research Diets Inc) for 12 weeks. Male data from our studies have been published previously, 30 so that the results from female offspring are the focus of this report. At 8 weeks of age, half of the female offspring fed either LFD or HFD were ovariectomized, thereby yielding 8 groups: (1) normotensive dam+LFD‐offspring, (2) normotensive dam+HFD‐offspring, (3) hypertensive dam+LFD‐offspring, (4) hypertensive dam+HFD‐offspring, (5) normotensive dam+LFD‐ovariectomized offspring, (6) normotensive dam+HFD‐ovariectomized offspring, (7) hypertensive dam+LFD‐ovariectomized offspring, and (8) hypertensive dam+HFD‐ovariectomized offspring.…”

“…Our previous study indicates that MHT induces hypertensive response sensitization (HTRS) elicited by postweaning HFD through a mechanism of exaggerated centrally driven sympathetic activity and the enhanced pressor responses to central leptin and RAS or PIC components in male offspring. 30 In the current study, we investigated if the maternal hypertension also induces HTRS elicited by postweaning HFD in female offspring. Furthermore, we determined if estrogen plays a protective role in MHT‐induced HTRS, and if estrogen protection is associated with regulation of brain reactivity to pressor agents and altered autonomic function in postweaning HFD fed female offspring.…”