Intrauterine hypoxia resulting from decreased maternal oxygen uptake, insufficient oxygen carrying capacity, or compromised oxygen delivery to the fetus jeopardizes fetal oxygen delivery, detrimentally affecting growth and development of the immature vasculature. Hypoxia transiently increases Hypoxia Inducible Factor-1α (HIF- 1α), which complexes with HIF-1β to form the active HIF-1 dimer that can affect transcription. This temporary rise in HIF-1 can promote gene transcription of ligands such as Vascular Endothelial Growth Factor (VEGF) and Endothelin-1 (ET-1), which rises and falls with HIF levels. The absence of chronic elevation of these ligands prompted the question of how long-term effects of hypoxia is sustained. Results suggest that in addition to stimulating transient rises in ligand levels, hypoxia alters receptor expression and coupling of these ligands to the intracellular kinases. Endothelin-1 (ET-1) is an established vasoconstrictor that can activate ETA or ETB receptors, respectively stimulating vasoconstriction and vasodilation. ET-1 activates pathways such as Protein Kinase C (PKC), Ca2+/Calmodulin-Dependent Protein Kinase (CaMK), p38, and MEK/ERK, which are involved in cellular growth, proliferation, and differentiation. Our results demonstrate that chronic hypoxia altered ovine fetal cerebrovascular reactivity to ET-1 but not plasma ET-1 levels or ETA receptor cerebrovascular
expression. However, chronic hypoxia enhances ET-1-induced contractility in an ETAdependent manner in Middle Cerebral Arteries (MCAs). ET-1 also exerts trophic effects on ovine fetal cerebrovasculature in organ culture in a PKC-dependent manner by inducing hypertrophy and increasing medial thicknesses, more in normoxic than hypoxic MCAs. ET-1-induced increase in arterial wall thickness is mediated by CaMKII and p38 dependent pathways in normoxic but not hypoxic arteries. Additionally, Myosin Light Chain Kinase (MLCK) and Smooth Muscle Alpha Actin (SMαA) colocalization data shows that ET-1 promotes contractile dedifferentiation in normoxic but not hypoxic MCAs in a PKC, CaMKII, and p38 dependent manner. These results support the notion that chronic hypoxia has long term effects mediated by altered receptor expression levels and intracellular coupling. A better understanding of how chronic hypoxia affects ET-1- induced intracellular coupling will help identify potential targets for future therapies to prevent and potentially treat remodeling of cerebral arteries in infants exposed to intrauterine hypoxia.
School of Medicine
Pearce, William J.
Nauli, Surya M.
Doctor of Philosophy (PhD)
Year Degree Awarded
Date (Title Page)
Library of Congress/MESH Subject Headings
Fetal Hypoxia; Cardiovascular system; Vascular Remodeling; Endothelium; Vascular; Sheep
Subject - Local
Cerebral Arteries; Intrauterine hypoxia; Hypoxia Inducible Factor; Vascular endothelial Growth Factor
Loma Linda University Libraries
This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.
Silpanisong, Jinjutha, "Endothelin-1 and Hypoxic Vascular Remodeling in Ovine Fetal Cerebral Arteries" (2017). Loma Linda University Electronic Theses, Dissertations & Projects. 523.
Loma Linda University Electronic Theses and Dissertations
Loma Linda University. Del E. Webb Memorial Library. University Archives