Chronic fetal hypoxia is common in obstetric pathologies, and produces numerous metabolic, endocrine and functional changes in the developing fetus. Among these, vascular remodeling is one ofthe most widely studied, particulariy in the fetal pulmonary and cerebral circulations, as we have demonstrated. Whereas functional consequences of hypoxic vascular remodeling have been examined in detail, the primary mechanisms driving hypoxic vascular remodeling remain unclear and largely unstudied. Based on evidence that Vascular Endothelial Growth Factor (VEGF) is increased by hypoxia, and can exert trophic effects on non-endothelial cells, this proposal explores the hypothesis that the effects of chronic hypoxia on arterial structure and function are mediated via both direct and indirect trophic effects of VEGF on vascular smooth muscle. This main hypothesis gives rise to three corollaries. The first corollary predicts that chronic hypoxia enhances the direct trophic effects of VEGF on vascular smooth muscle.
Specific Aim 1 will use normoxic and hypoxic organ cultures of endothelium-denuded fetal cerebral arteries to determine the direct trophic effects of VEGF on smooth muscle as mediated by either Flk-1 or Flt-1 receptors, PI3-Kinase or MAP-Kinase pathways. The second corollary predicts that chronic hypoxia enhances the ability of VEGF to exert indirect trophic effects on vascular smooth muscle through direct effects on arterial endothelium.
Specific Aim 2 will use normoxic and hypoxic organ cultures of endothelium-intact fetal cerebral arteries to define the role of endothelial release of NO and endothelin-1 in the effects of VEGF on cerebrovascular smooth muscle as defined by the effects ofthe NO donor SNAP, the Protein Kinase G activator 8-pCPTcGMP, the NO synthase inhibitor L-NAME, endothelin-1 and the selective endothelin antagonist BQ-123. The third corollary predicts that chronic hypoxia enhances the ability of VEGF to exert indirect trophic effects on vascular smooth muscle through direct effects on the perivascular sympathetic innervation.
Specific Aim 3 will use normoxic and hypoxic organ cultures of endothelium-intact and endothelium-denuded cerebral arteries from fetuses denervated via superior cervical ganglionectomy at 128 d gestation and harvested 14 days later to determine the direct effects of norepinephrine and neuropeptide-Y. All experiments will analyze responses to VEGF via changes in: 1) contractility via active and passive stress-strain measurements;2) abundances of 6 different contractile proteins (a-actin. Myosin Light Chain Kinase, 20 kDa Myosin Light Chain, SMI myosin, SM2 myosin, and non-muscle myosin) measured via Western blots;and 3) morphometry of the transmural distribution of the 6 contractile proteins using calibrated fluorescent immunohistochemistry. These experiments will enable an unprecedented evaluation of the non-angiogenic effects of VEGF and their roles in fetal cerebrovascular remodeling responses to chronic hypoxia.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD031226-20
Application #
8704964
Study Section
Special Emphasis Panel (ZHD1)
Project Start
Project End
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
20
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Loma Linda University
Department
Type
DUNS #
City
Loma Linda
State
CA
Country
United States
Zip Code
92354
Vrancken, Kurt; Schroeder, Hobe J; Longo, Lawrence D et al. (2016) Postprandial lipids accelerate and redirect nitric oxide consumption in plasma. Nitric Oxide 55-56:70-81
Liu, Taiming; Schroeder, Hobe J; Wilson, Sean M et al. (2016) Local and systemic vasodilatory effects of low molecular weight S-nitrosothiols. Free Radic Biol Med 91:215-23
Blum-Johnston, Carla; Thorpe, Richard B; Wee, Chelsea et al. (2016) Developmental acceleration of bradykinin-dependent relaxation by prenatal chronic hypoxia impedes normal development after birth. Am J Physiol Lung Cell Mol Physiol 310:L271-86
Hu, Xiang-Qun; Huang, Xiaohui; Xiao, Daliao et al. (2016) Direct effect of chronic hypoxia in suppressing large conductance Ca(2+)-activated K(+) channel activity in ovine uterine arteries via increasing oxidative stress. J Physiol 594:343-56
Myers, Dean A; Singleton, Krista; Kenkel, Christy et al. (2016) Gestational hypoxia modulates expression of corticotropin-releasing hormone and arginine vasopressin in the paraventricular nucleus in the ovine fetus. Physiol Rep 4:
Mata-Greenwood, Eugenia; Jackson, P Naomi; Pearce, William J et al. (2015) Endothelial glucocorticoid receptor promoter methylation according to dexamethasone sensitivity. J Mol Endocrinol 55:133-46
Newby, Elizabeth A; Kaushal, Kanchan M; Myers, Dean A et al. (2015) Adrenocorticotropic Hormone and PI3K/Akt Inhibition Reduce eNOS Phosphorylation and Increase Cortisol Biosynthesis in Long-Term Hypoxic Ovine Fetal Adrenal Cortical Cells. Reprod Sci 22:932-41
Chuang, Tsai-Der; Pearce, William J; Khorram, Omid (2015) miR-29c induction contributes to downregulation of vascular extracellular matrix proteins by glucocorticoids. Am J Physiol Cell Physiol 309:C117-25
Adeoye, Olayemi O; Silpanisong, Jinjutha; Williams, James M et al. (2015) Role of the sympathetic autonomic nervous system in hypoxic remodeling of the fetal cerebral vasculature. J Cardiovasc Pharmacol 65:308-16
Myers, Dean A; Singleton, Krista; Hyatt, Kim et al. (2015) Long-Term Gestational Hypoxia Modulates Expression of Key Genes Governing Mitochondrial Function in the Perirenal Adipose of the Late Gestation Sheep Fetus. Reprod Sci 22:654-63

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