Intrauterine growth restriction is a significant cause of fetal and neonatal mortality and morbidity and is major health-related problems in the U.S. Growth-restricted infants that survive the neonatal period have an increased risk of lifelong complications, including a range of metabolic, neurological, and cardiovascular disorders. Epidemiological studies throughout the world support the concept of """"""""developmental programming"""""""" of cardiovascular disease by showing that the risks of developing disorders such as hypertension, stroke, and coronary heart disease are inversely related to birth weight. The mechanisms underlying the programming of cardiovascular diseases are poorly understood, but emerging evidence suggests that a poor nutrient supply at critical periods of early development leads to permanent alterations in vascular structure or function. The present application is aimed at beginning to address this issue in a mechanistic manner, and is centered on the general concept of endothelial dysfunction in coronary arteries. We hypothesize that compromised nutrition during fetal development may lead to permanent adverse changes in vascular function that increase the risk for cardiovascular disease later in life. More specifically, we propose that maternal nutrient restriction during pregnancy selectively impairs a novel endothelium- dependent, NO-independent (i.e. EDHF-like) vasodilator pathway that is mediated by activation of large conductance, calcium-activated K channels (BKCa) in fetal coronary arteries. We have set forth two specific aims that address our primary objective of determining the mechanism(s) whereby maternal nutrition during pregnancy alters endothelial regulation of coronary arterial tone.
In Aim #1 we will identify the role of BKCa channels in mediating relaxation of fetal coronary arteries from animals that are well-nourished and undernourished in utero. This hypothesis will be directly addressed by determining BKCa channel gene and protein expression, BKCa channel activity, and vascular function in fetal coronary arteries.
In Aim #2 we will establish whether maternal nutrient restriction during pregnancy results in dysfunction of the putative EDHF vasodilator pathway in the offspring. This hypothesis will be addressed by comparing endothelium- dependent vasodilator responses in coronary arteries from 6-month old animals that were well-nourished and undernourished in utero. BKCa channel gene and protein expression and BKCa channel activity will also be measured in these arteries. The results of these studies will establish whether the BKCa channels are defective in the fetuses and offspring or whether the EDHF system itself is compromised, and thus will give us clear future directions. The knowledge gained will provide key preliminary data that will put us in position to pursue more detailed, long-term mechanistic studies of the impact of fetal nutrition on cardiovascular function in health and disease.

Public Health Relevance

Low birthweight babies have an increased risk of developing cardiovascular diseases later in life. Emerging evidence suggests that a poor nutrient supply at critical periods of early development leads to permanent alterations in blood vessel structure or function. This study will address potential mechanisms by which undernutrition during pregnancy impacts coronary arteries, and may serve as the basis for developing new strategies for preventing or reversing disorders such as hypertension and coronary artery disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Small Research Grants (R03)
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Pediatrics Subcommittee (CHHD)
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Grave, Gilman D
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North Dakota State University
Schools of Pharmacy
United States
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Peine, Jena L; Jia, Guangquiang; Van Emon, Megan L et al. (2018) Effects of maternal nutrition and rumen-protected arginine supplementation on ewe performance and postnatal lamb growth and internal organ mass. J Anim Sci 96:3471-3481
Shukla, Praveen; Ghatta, Srinivas; Dubey, Nidhi et al. (2014) Maternal nutrient restriction during pregnancy impairs an endothelium-derived hyperpolarizing factor-like pathway in sheep fetal coronary arteries. Am J Physiol Heart Circ Physiol 307:H134-42