The Role of VEGF and Smooth Muscle Phenotype in Hypoxic Remodeling of Ovine Carotid and Cerebral Arteries

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Hubbell, Margaret C.
Vascular remodeling; Endothelial regulation; VEGF; Vascular Endothelial Growth Factor; Vascular Smooth Muscle Cell; Medical Biochemistry; Medical Sciences; Medicine and Health Sciences; Hypoxia-Ischemia, Brain - Physiopathology; Endothelium, Vascular; Muscle, Smooth, Vascular; Cardiovascular System - Physiopathology; Fetal Hypoxia - Physiopathology;
thesis / dissertation description
Arteries are a dynamic tissue with multiple cell types that incorporate systemic and local factors to maintain homeostasis. Hypoxia stimulates capillary angiogenesis to effectively match metabolic demand with perfusion. With chronic hypoxia, vascular remodeling of even large vessels can occur. This predisposes to pathologic states as seen with atherosclerosis, hypoxic brain injury, myocardial ischemia, diabetes, and developmental anomalies. With this remodeling comes changes in vessel structure including medial thickness and organization of contractile proteins as well as changes in myogenic tone. All of these factors culminate in changes in status or behavior of the vascular smooth muscle within the vessel wall, likely secondary to changes in smooth muscle phenotype. This investigation examines the hypothesis that hypoxia induces vascular remodeling through transformation of vascular smooth muscle cell phenotype mediated by VEGF action directly on smooth muscle and indirectly through the endothelium. This was performed with harvested middle cerebral and common carotid arteries from fetal and adult sheep after exposure to a hypoxic setting (3280m for 110 days) or normoxic setting (sea level). These arteries were then subjected to endothelial denudation or left intact and then underwent structural and functional contractility assays, immunoblotting, and immunohistochemistry either immediately after harvest or following in vitro treatment with organ culture. Hypoxia and VEGF in organ culture had similar effects on contractile function and reorganization of contractile proteins including mature and immature myosin heavy chains (MHC) isoforms, Smooth muscle-MHC and Non-muscle MHC respectively with Smooth muscle-alpha Actin (SM-AA). The endothelium appeared to be a significant component of VEGF alterations to contractile function and MHC:SM-AA re-organization and this was mediated in part through VEGF stimulation of the NO pathway. Hypoxic acclimatization was found to not only alter acute responses to contractile stimulants but to alter reactivity to future insults with VEGF. In conclusion, hypoxic vascular remodeling significantly alters vascular SMC function and phenotype through VEGF and endothelial regulation.