Persistent pulmonary hypertension or the newborn (PPHN) is characterized by failure of the pulmonary circulation to achieve or sustain the normal decrease in pulmonary vascular resistance (PVR) at birth. Mechanisms that contribute to the pathogenesis and pathophysiology of PPHN are uncertain, but include abnormalities of vascular function (""""""""maladaptation""""""""), structure (""""""""maldevelopment""""""""), and growth (""""""""underdevelopment""""""""). Vascular endothelial growth factor (VEGF) is a potent endothelial cell mitogen and a critical trophic factor for the maintainence of normal endothelial function. Past studies in mouse models of lung development have clearly shown that VEGF plays an essential role in vasculogenesis and angiogenesis during the early embryonic period, but little is known about the role of VEGF and its KDR receptor in vascular growth and endothelial function in the pulmonary circulation during late gestation. The endothelial cell plays a central role in the regulation of the normal fetal and transitional pulmonary circulations, especially through production of nitric oxide (NO). NO modulates basal PVR in the normal fetus, contributes to the fall in PVR at birth, and is decreased in experimental models of PPHN. However, mechanisms that regulate endothelial function and NOS expression in the perinatal lung are poorly understood. In vitro studies suggest that VEGF mediates endothelial cell growth through NO-dependent mechanisms, and that VEGF can upregulate NO synthase (NOS) expression in some settings. Whether the VEGF-KDR system plays a critical role in angiogenesis endothelial cell survival and function, and the regulation of NOS expression during late fetal life, is unknown. Therefore, we hypothesize that the VEGF-KDR axis is critical for normal lung vascular growth, and that disruption of VEGF production or activity impairs pulmonary vascular development, leading to decreased endothelial cell growth and function, and failure of postnatal adaptation at birth. To test these hypotheses, we propose to investigate the following specific aims: 1) to define normal temporal and cell-specific changes in VEGF-KDR expression during lung maturation in the fetal and postnatal lung; 2) to determine whether abnormal homodynamic stress disrupts normal vascular growth in utero, decreases VEGF and KDR expression and activities, and contributes to failure of postnatal adaptation at birth; 3) to determine whether inhibition of VEGF or the KDR receptor disrupts lung vascular growth, alters vasoreactivity, and causes pulmonary hypertension; and 4) whether VEGF treatment improves endothelial function and vascular growth in experimental PPHN. Studies will utilize the chronically-prepared fetal lamb model to provide an integrative physiologic approach that combines whole animal physiology with molecular, biochemical, and morphometric studies.
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