Perinatal Iron Deficiency Combined With a High Salt Diet in Adulthood Causes Sex-Dependent Vascular Dysfunction and Oxidative Stress
Introduction: Iron deficiency (ID) is the most common nutritional deficiency worldwide, for which pregnant women are most at risk. We have previously shown that perinatal ID causes hypertension and renal dysfunction in adult offspring. Here, we sought to determine whether perinatal ID would impact mesenteric artery function and oxidative stress in adult offspring; furthermore, we evaluated whether effects are exacerbated a chronic consumption of a high-salt diet — a cardiovascular stress common in developed nations.
Methods: six-week old Sprague Dawley dams were fed either an iron-restricted (3-10mg/kg Fe; perinatal ID group) or an iron-replete diet (37 mg/kg Fe; control group) prior to and throughout pregnancy. At birth, all rats were fed an iron-replete diet. At 4.5 months of age, ID and control offspring were fed either a normal-salt (0.26% NaCl w/w) or high-salt (HS; 5% NaCl w/w) diet for 6 weeks prior to experimentation. Mesenteric artery function was assessed by wire myography. Superoxide and nitric oxide (NO) levels in cryopreserved vessels were assessed using dihydroethidium and 4-Amino-5-methylamino-2’,7’-difluorofluorescein staining, respectively.
Results: Offspring born to iron-restricted dams were growth restricted (-11% bodyweight; P<0.05) and anemic (-40% hemoglobin; P<0.001) independent of sex. Adult male perinatal ID offspring exhibited decreased reliance on NO for methacholine-induced vasodilation (P=0.03), coincident with increased superoxide levels when fed a HS diet (P=0.01). Male perinatal ID offspring exhibit enhanced conversion of big endothelin-1 to active endothelin-1 (P=0.02) concomitant with decreased NO levels (P=0.005). Female offspring vascular function was unaffected by either perinatal ID or HS diet, albeit HS diet was associated with decreased NO production (P=0.02), particularly in the perinatal ID offspring.
Conclusion: Perinatal ID and a subsequent HS diet in adulthood impact male offspring vascular function to a greater extent than female offspring, and these effects may be mediated, at least in part, by increased vascular oxidative stress.