Mechanisms of endothelium-dependent vasodilation in male and female, young and aged offspring born growth restricted

Morton JS, Rueda-Clausen CF, Davidge ST. Mechanisms of endothelium-dependent vasodilation in male and female, young and aged offspring born growth restricted. Am J Physiol Regul Integr Comp Physiol 298: R930-R938, 2010. First published January 6, 2010; doi: 10.1152/ajpregu.00641.2009.-Numerous epidemiological studies have shown that cardiovascular dysfunction in adult life may be programmed by compromised growth in utero. Aging is a risk factor for vascular endothelial-dependent dysfunction. After birth, the impact of intrauterine growth restriction (IUGR) on normal aging mechanisms of vascular dysfunction is not known. We hypothesized that IUGR would cause changes in vascular function that would affect the mechanisms of endothelium-dependent vasodilation later in life in an age-or sex-dependent manner. To create an IUGR model, pregnant Sprague-Dawley rats were placed in a hypoxic (12% O-2) or control (room air, 21% O-2) environment from days 15 to 21 of the pregnancy, and both male and female offspring were investigated at 4 or 12 mo of age. Endothelial function was assessed in small mesenteric arteries using methacholine (MCh)-induced vasodilation in a wire myograph system. The involvement of nitric oxide (NO), prostaglandins, and endothelium-derived hyperpolarizing factor (EDHF) was assessed using the inhibitors N-omega-nitro-L-arginine methyl ester hydrochloride, meclofenamate, or a combination of apamin and TRAM-34 (SKCa and IKCa blockers), respectively. EDHF-induced vasodilation was further investigated by using inhibitors of P450 epoxygenases [N-methylsulfonyl-6-( 2-propargyloxyphenyl) hexanamide] and gap junctions (18 alpha-glycyrrhetinic acid). NO-mediated vasodilation was significantly reduced in aged controls and both young and aged IUGR females. EDHF-mediated vasodilation was maintained in all groups; however, an additional involvement of gap junctions was found in females exposed to hypoxia in utero, which may represent a compensatory mechanism. A change in the mechanisms of vasodilation occurring at an earlier age in IUGR offspring may predispose them to adult cardiovascular diseases.