Numerous epidemiological studies report an inverse relationship between low birth weight (LBW) and the risk of hypertension; however, the mechanisms linking LBW and hypertension remain unclear. The kidneys are known to play an important role in the long-term regulation of arterial pressure. An important role for the kidneys in the programming of hypertension is suggested as maternal protein restriction administered during nephrogenesis or the last third of gestation in the rat, results in hypertensive LBW offspring that are associated with alterations in the renin angiotensin system (RAS) and the sympathetic nervous system (SNS). Thus, animal models of fetal malnutrition induced by maternal protein restriction during gestation support a role for programming of hypertension due to an adverse fetal environment. In humans, fetal malnutrition, due to either an insufficient nutrient delivery via reduced uteroplacental perfusion or maternal undernutrition, limits fetal growth and results in small-for-gestational-age newborn. As LBW within the Western world is more likely the result of impaired uteroplacental perfusion rather than maternal malnutrition, we have developed a unique model of in vivo placental insufficiency to examine the association between LBW and hypertension. Specifically, reduced uterine perfusion induced during late gestation in the rat results in LBW offspring born at term that develop hypertension, and based on preliminary data, exhibit alterations in both the RAS and SNS. Thus, adaptations to oxygen and nutrient restriction during a critical period of fetal development may lead to programming with resulting activation of the RAS and SNS leading to the development of hypertension. Thus, we will utilize our novel animal model to test the central hypothesis that hypertension in LBW offspring is initiated and sustained by abnormalities in the RAS and the SNS. To test this hypothesis, we plan to characterize temporal changes in the RAS and SNS, and directly assess the role of these systems in the pathogenesis of the hypertension utilizing molecular and physiological methods.
Specific aims to be addressed are: 1. To test the hypothesis that abnormalities in the RAS mediate the hypertension in LBW offspring. 2. To test the hypothesis that abnormalities in the SNS mediate the hypertension in LBW offspring. 3. To determine the temporal interactions between the SNS and the RAS in mediating hypertension in LBW offspring. ? ?
|Newsome, Ashley D; Davis, Gwendolyn K; Ojeda, Norma B et al. (2017) Complications during pregnancy and fetal development: implications for the occurrence of chronic kidney disease. Expert Rev Cardiovasc Ther 15:211-220|
|Davis, Gwendolyn K; Newsome, Ashley D; Ojeda, Norma B et al. (2017) Effects of Intrauterine Growth Restriction and Female Sex on Future Blood Pressure and Cardiovascular Disease. Curr Hypertens Rep 19:13|
|Dasinger, John Henry; Intapad, Suttira; Backstrom, Miles A et al. (2016) Intrauterine growth restriction programs an accelerated age-related increase in cardiovascular risk in male offspring. Am J Physiol Renal Physiol 311:F312-9|
|Dasinger, John Henry; Intapad, Suttira; Rudsenske, Benjamin R et al. (2016) Chronic Blockade of the Androgen Receptor Abolishes Age-Dependent Increases in Blood Pressure in Female Growth-Restricted Rats. Hypertension 67:1281-90|
|Intapad, Suttira; Dasinger, John Henry; Brown, Andrew D et al. (2016) Glucose intolerance develops prior to increased adiposity and accelerated cessation of estrous cyclicity in female growth-restricted rats. Pediatr Res 79:962-70|
|Dasinger, John Henry; Alexander, Barbara T (2016) Gender differences in developmental programming of cardiovascular diseases. Clin Sci (Lond) 130:337-48|
|Dasinger, John Henry; Davis, Gwendolyn K; Newsome, Ashley D et al. (2016) Developmental Programming of Hypertension: Physiological Mechanisms. Hypertension 68:826-31|
|Intapad, Suttira; Ojeda, Norma B; Varney, Elliott et al. (2015) Sex-Specific Effect of Endothelin in the Blood Pressure Response to Acute Angiotensin II in Growth-Restricted Rats. Hypertension 66:1260-6|
|Alexander, Barbara T; Dasinger, John Henry; Intapad, Suttira (2015) Fetal programming and cardiovascular pathology. Compr Physiol 5:997-1025|
|Alexander, Barbara T (2015) The Impact of Nutritional Insults during Fetal Life on Blood Pressure. J Nutr Sci Vitaminol (Tokyo) 61 Suppl:S5-6|
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