Adverse events occurring during fetal life can contribute to an increased risk of disease in adult life. Chronic intrauterine hypoxia causes fetal growth restriction and renders the offspring vulnerable to hypertension and heart disease as well as other complications. Thus, the developmental origins of health and disease (DOHaD) hypothesis has posited a critical role of prenatal care in etiologies of several disease conditions. Prenatal hypoxia has been shown to disrupt cardiovascular function through mechanisms associated with both heart and blood vessel pathologies. We have generated a well established hypoxic pregnant guinea pig model that exhibits fetal and offspring phenotype of mitochondrial dysfunction. Further, our data show that exposure to hypoxia during the fetal growth phase inhibits contractile function in the offspring heart. We propose that mitochondrial-specific mechanisms associated with biogenesis and bioenergetics in the fetal heart are inhibited, which is sustained in the offspring and manifest as cardiac ventricular dysfunction. We will determine the effects of prenatal hypoxia on mRNA/gene expression of the PGC1a/PPAR pathway and respiratory chain complex expression in fetal hearts. We will evaluate the sustained consequences of prenatal hypoxia on mitochondrial respiration in intact cardiac cells. Using live cell imaging with super-resolution confocal microscopy, we will identify the effects of prenatal hypoxia on mitochondrial structure, membrane integrity, and Ca2+ transients in cell contraction of cardiac cells from offspring hearts. We will evaluate ventricular dysfunction in the offspring hearts exposed to prenatal hypoxia by echocardiography and pressure-volume loop analysis. Finally, we will treat pregnant sows and neonates with nicotinamide modulators (resveratrol and nicotinamide riboside) to enhance the NAD+/NADH ratio, which is a central regulator of energy metabolism. We will determine whether treatment enhances mitochondrial function and/or contractile function of the offspring as a pharmacological approach for improving mitochondrial health and reducing the risk of heart disease.
Fetuses developing in adverse intrauterine environments, such as reduced oxygen levels termed hypoxia, face the risk of death if unable to adapt in utero. The adaptive response, however, has consequences of asymmetric growth restriction and organ dysfunction. The fetal heart exposed to prenatal hypoxia exhibits impaired energy generation, or ATP synthesis, originating from the mitochondria of the cardiac cell, which is critical for cardiac cell contraction. The goal of this proposal is to identify the mitochondrial mechanisms disrupted by prenatal hypoxia in the fetal heart, investigate their impact on cardiac contractile function in the offspring, and develop treatment regimens that will improve mitochondrial health and respiratory capacity in the affected offspring.
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|Thompson, Loren P; Chen, Ling; Polster, Brian M et al. (2018) Prenatal hypoxia impairs cardiac mitochondrial and ventricular function in guinea pig offspring in a sex-related manner. Am J Physiol Regul Integr Comp Physiol :|
|Turan, Sifa; Aberdeen, Graham W; Thompson, Loren P (2017) Chronic hypoxia alters maternal uterine and fetal hemodynamics in the full-term pregnant guinea pig. Am J Physiol Regul Integr Comp Physiol 313:R330-R339|
|Thompson, Loren P; Pence, Laramie; Pinkas, Gerald et al. (2016) Placental Hypoxia During Early Pregnancy Causes Maternal Hypertension and Placental Insufficiency in the Hypoxic Guinea Pig Model. Biol Reprod 95:128|