Human epidemiological studies have shown a clear association of adverse intrauterine environment and an increased risk of ischemic heart disease in later adult life. Of all the stresses to which the fetus is subjected, perhaps the most important and clinically relevant is that of hypoxia. The goal of this project is to test the hypothesis that chronic hypoxia during gestation adversely affects fetal cardiovascular development and impairs cardiac function in offspring. In the first part of project, we tested the hypothesis that chronic hypoxia adversely regulates contractility of fetal pulmonary arteries and veins in sheep residing at high altitude (3,801 m) for 110 days. Our studies demonstrate the heterogeneity of fetal pulmonary arteries and veins in response to long-term high altitude hypoxia and suggest a likely common mechanism downstream of nitric oxide in fetal pulmonary vascular response to chronic hypoxia in utero, which may be associated with an increased risk of pulmonary hypertension observed in newborn caused by fetal hypoxia. The second part of project focused on the effect of fetal hypoxia on heart development. This was accomplished by using a rat model. Time-dated pregnant rats were divided between normoxic and hypoxia (10.5% 02 on days 15-21 of gestation). We demonstrated that prenatal hypoxia caused an increase in heart susceptibility to ischemia and reperfusion injury in male offspring in a sex-dependent manner. This was caused by enhanced type 2 angiotensin II receptors (ATiR) and reduced PKCε expression in the heart. Further studies revealed an important role of glucocorticoid in programming of angiotensin II receptors, resulting in increased ischemic vulnerability in the heart of offspring. Multiple glucocorticoid response elements (GREs) were identified at the AT2R promoter, deletion of which increased the promoter activity. Consistently, we demonstrated that dexamethasone decreased AT2R expression in the fetal heart, which was blocked by RU 486. Prenatal hypoxia decreased glucocorticoid receptor (OR) expression in adult hearts, resulting in decreased GR binding to the GREs at the AT2R promoter. These findings provide a mechanistic understanding worth of investigation in humans in fetal origins of cardiovascular disease caused by intrauterine adverse environment.
John N. Buchholz
Arlin B. Blood
Charles A. Ducsay
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Fetal Hypoxia -- physiopathology; Fetal Heart -- physiopathology; Fetal Development; Hypoxia-Ischemia, Brain -- physiopathology; Cardiovascular System -- physiopathology; Coronary Vessels; Endothelium, Vascular; Gene Expression Regulation -- genetics; RNA, Messenger -- genetics; Nitric Oxide Synthase; Protein Kinase C -- pharmacology; Blotting, Western; Animals; Sheep; Rats, Sprague-Dawley.
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Xue, Qin, "Hypoxia and Fetal Programming of Cardiovascular Dysfunction" (2010). Loma Linda University Electronic Theses, Dissertations & Projects. 1648.
Loma Linda University Electronic Theses and Dissertations
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