At every stage of life the regulation of cerebral vascular tone and blood flow (CBF) is of vital importance. Many newborn infants, particularly those that are premature, have serious problems in the regulation of blood flow to their brains. This dysregulation may have serious consequences with intraventricular and germinal matrix hemorrhage with long-term neurological sequelae. The present studies seek to understand whereby maturational development alters fundamental signal transduction mechanisms in the cerebrovasculature of the fetus/premature newborn and the adult. This project is broadly based, multidisciplinary, and vertically integrated using physiologic, cellular, biochemical, and molecular approaches. Based on several decades of research findings, we shall test the overall hypothesis that maturational development is associated with significant changes in cerebral artery (CA) contractile responses secondary to altered alpha1-adrenergic-receptor (1-AR) subtype and/or specific protein kinase C isoform (PKC)-mediated downstream Ca2+-dependent and Ca2+-independent signal transduction pathways. An associated hypothesis is that development significantly alters 1-AR-subtype- and specific PKC isozyme-mediated expression of proto-oncogenes and genes representing vascular smooth muscle """"""""synthetic"""""""" and/or """"""""proliferative"""""""" phenotypes, as compared to adult """"""""contractile"""""""" phenotype.
Four Specific Aims are as follows. 1) What is the role of specific 1-AR subtypes and downstream effector proteins in signal transduction? 2) What is the role of specific PKC isoforms, extracellular signal regulated kinases (ERKs), Rho A/Rho kinases, and related kinases in signal transduction? 3) What is the role of specific 1-AR subtypes and PKC isoforms in gene regulation of developing vascular phenotypes? 4) What is the role of other signal transduction proteins presently poorly described in these signal transduction and gene regulation pathways? In ovine fetal, newborn, and adult CA, we will perform agonist-induced contractility and intracellular [Ca2+] measurements, Western immunoblots, RT- PCR, confocal microscopy, flow cytometry, 2D-gel-mass spectroscopy, gene silencing by double stranded RNA or morpholinos, gene upregulation, gene microarray/pathway analysis, and gene/protein discovery. Scientifically, the studies will advance our understanding of basic mechanisms whereby cerebral vessels change phenotypically and functionally with development from fetus, to newborn, to adult. Clinically, the studies relate to understanding the basis of the regulation of cerebral vascular tone, pressure, and blood flow in the fetus and/or premature newborn infant, and its dysregulation that results in intracerebral hemorrhage and serious neurologic sequelae.

Public Health Relevance

At every stage of life, regulation of blood flow to the brain is of critical importance. Many infants, particularly those that are premature, suffer from dysregulation of cerebrovascular blood flow with intracerebral hemorrhage and severe long-term neurological sequelae. Scientifically, the proposed studies will augment our understanding of basic mechanisms whereby blood vessels to the brain of fetus, premature newborn, and adult change with developmental maturation. From a clinical standpoint, these studies relate to important problems such as the regulation of brain blood flow and metabolism in fetus and newborn infant, their responses to hypoxia as occurs in women who smoke, as well as those who are anemic, or who have heart or lung disease, and the mechanisms of maternal stress and prenatal programming.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Special Emphasis Panel (ZRG1-EMNR-K (02))
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Raju, Tonse N
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Loma Linda University
Other Basic Sciences
Schools of Medicine
Loma Linda
United States
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Goyal, Ravi; Goyal, Dipali; Longo, Lawrence D et al. (2016) Microarray gene expression analysis in ovine ductus arteriosus during fetal development and birth transition. Pediatr Res 80:610-8
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
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
Dobyns, Abigail E; Goyal, Ravi; Carpenter, Lauren Grisham et al. (2015) Macrophage gene expression associated with remodeling of the prepartum rat cervix: microarray and pathway analyses. PLoS One 10:e0119782
Tao, Xiaoxiao; Lin, Mike T; Thorington, Glyne U et al. (2015) Long-term hypoxia increases calcium affinity of BK channels in ovine fetal and adult cerebral artery smooth muscle. Am J Physiol Heart Circ Physiol 308:H707-22
Goyal, Ravi; Longo, Lawrence D (2014) Acclimatization to long-term hypoxia: gene expression in ovine carotid arteries. Physiol Genomics 46:725-34
Goyal, Ravi; Goyal, Dipali; Chu, Nina et al. (2014) Cerebral artery alpha-1 AR subtypes: high altitude long-term acclimatization responses. PLoS One 9:e112784
Blood, Arlin B; Terry, Michael H; Merritt, Travis A et al. (2013) Effect of chronic perinatal hypoxia on the role of rho-kinase in pulmonary artery contraction in newborn lambs. Am J Physiol Regul Integr Comp Physiol 304:R136-46
Goyal, Ravi; Van Wickle, Jonathan; Goyal, Dipali et al. (2013) Antenatal maternal long-term hypoxia: acclimatization responses with altered gene expression in ovine fetal carotid arteries. PLoS One 8:e82200
Longo, Lawrence D; Goyal, Ravi (2013) Cerebral artery signal transduction mechanisms: developmental changes in dynamics and Ca2+ sensitivity. Curr Vasc Pharmacol 11:655-711

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