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.
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