Fetal hypoxia is believed to be an important pathogenetic factor in a number of pregnancy-related complications such as preeclampsia and intrauterine growth restriction (IUGR). Numerous epidemiological and animal studies have shown that stressors such as hypoxia can influence the growth and developmental trajectories of the fetus, thereby increasing its susceptibility to long-term health complications, including cardiovascular diseases (reviewed in Rueda-Clausen et al 1 ). In support of this, we and others have shown that prenatal hypoxia is associated with long-term alterations in vascular function, characterized by reduced NO-mediated vasodilation, as well as increased responsiveness to adrenergic vasoconstrictors. [2][3][4] ET-1 is a polypeptide that plays an integral role in vascular function. By virtue of its potent vasoconstrictor properties and its capacity to induce vascular remodeling, ET-1 signaling is believed to be important in the progression of diseases where vascular dysfunction plays a role. 5,6 The vasoactive peptide ET-1 is synthesized as an inactive precursor, big ET-1 (bET-1), which is then subsequently cleaved by 1 of several enzymes, including the endothelin (ET)-converting enzymes (ECE), certain members of the matrix-metalloproteinase (MMP) family (notably the gelatinases), chymase and neutral endopeptidase. 7 Recently, we showed that NO plays a role in regulating the conversion of bET-1 to active ET-1, 8 and consequently conditions of NO deficiency, such as IUGR, may also be associated with increased ET-1 activity. Collectively, these studies provided us the impetus to investigate whether prenatal hypoxia confers on the offspring an altered circulatory phenotype, characterized by increased ET-1 signaling, and determine whether male and female offspring were similarly affected. MethodsExpanded methods are available in the online-only Data Supplement. Briefly, the experimental protocols described herein were approved by the University of Alberta Health Sciences Animal Policy and Welfare Committee in accordance with the See Editorial Commentary, pp 685-686Abstract-Prenatal hypoxia can alter the growth trajectory of the fetus and cause lasting health complications including vascular dysfunction. We hypothesized that offspring that were intrauterine growth restricted (IUGR) because of prenatal hypoxia would exhibit altered vascular endothelin-1 (ET-1) signaling in later life. Isolated mesenteric artery responses to big ET-1 (bET-1) and ET-1 were assessed by using wire myography. Male IUGR offspring had 3-fold greater bET-1-induced vasoconstriction compared with controls (n=7 per group; P<0.001); NO synthase inhibition with L-N G -nitroarginine-methyl ester potentiated bET-1-induced vasoconstriction, albeit this effect was 2-fold greater (P<0.05) in male control compared with IUGR offspring. Vascular responses to bET-1 were similar between female IUGR and control offspring (n=9-11 per group). In the presence of L-N G -nitro-arginine-methyl ester, pretreatment with the chymase inhibitor chymosta...

Prenatal iron-deficiency (ID) is known to alter fetal developmental trajectories, which predisposes the offspring to chronic disease in later life, although the underlying mechanisms remain unclear. Here, we sought to determine whether varying degrees of maternal anaemia could induce organ-specific patterns of hypoxia in the fetuses. Pregnant female Sprague Dawley rats were fed iron-restricted or iron-replete diets to induce a state of moderate (M-ID) or severe ID (S-ID) alongside respective controls. Ultrasound biomicroscopy was performed on gestational day (GD)20 to assess uterine and umbilical artery blood flow patterns. On GD21, tissues were collected and assessed for hypoxia using pimonidazole staining. Compared to controls, maternal haemoglobin (Hb) in M- and S-ID were reduced 17% (P < 0.01) and 48% (P < 0.001), corresponding to 39% (P < 0.001) and 65% (P < 0.001) decreases in fetal Hb. Prenatal ID caused asymmetric fetal growth restriction, which was most pronounced in S-ID. In both severities of ID, umbilical artery resistive index was increased (P < 0.01), while pulsatility index only increased in S-ID (P < 0.05). In both M-and S-ID, fetal kidneys and livers showed evidence of hypoxia (P < 0.01 vs. controls), whereas fetal brains and placentae remained normoxic. These findings indicate prenatal ID causes organ-specific fetal hypoxia, even in the absence of severe maternal anaemia.

The risk of developing cardiovascular diseases is known to begin before birth and the impact of the intrauterine environment on subsequent adult health is currently being investigated from many quarters. Following our studies demonstrating the impact of hypoxia in utero and consequent intrauterine growth restriction (IUGR) on the rat cardiovascular system, we hypothesized that changes extend throughout the vasculature and alter function of the renal artery. In addition, we hypothesized that hypoxia induces renal senescence as a potential mediator of altered vascular function. We demonstrated that IUGR females had decreased responses to the adrenergic agonist phenylephrine (PE; pEC50 6.50 ± 0.05 control v. 6.17 ± 0.09 IUGR, P < 0.05) and the endothelium-dependent vasodilator methylcholine (MCh; E max 89.8 ± 7.0% control v. 41.0 ± 6.5% IUGR, P < 0.001). In IUGR females, this was characterised by increased basal nitric oxide (NO) modulation of vasoconstriction (PE pEC50 6.17 ± 0.09 IUGR v. 6.42 ± 0.08 in the presence of the NO synthase inhibitor N-nitro-l-arginine methyl ester hydrochloride (l-NAME; P < 0.01) but decreased activated NO modulation (no change in MCh responses in the presence of l-NAME), respectively. In contrast, IUGR males had no changes in PE or MCh responses but demonstrated increased basal NO (PE pEC50 6.29 ± 0.06 IUGR v. 6.42 ± 0.12 plus l-NAME, P < 0.01) and activated NO (E max 37.8 ± 9.4% control v. -0.8 ± 13.0% plus l-NAME, P < 0.05) modulation. No significant changes were found in gross kidney morphology, proteinuria or markers of cellular senescence in either sex. In summary, renal vascular function was altered by hypoxia in utero in a sex-dependent manner but was unlikely to be mediated by premature renal senescence.

Genome editing technologies promise therapeutic advances for genetic diseases. We discuss the ethical and societal issues raised by these technologies, including their use in preclinical research, their potential to address mutations in somatic cells, and their potential to make germ line alterations that may be passed to subsequent generations. We call for a proportionate response from health leaders based on a realistic assessment of benefits, risks, and timelines for clinical translation.