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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD003807-41
Application #
8606474
Study Section
Special Emphasis Panel (ZRG1-EMNR-K (02))
Program Officer
Raju, Tonse N
Project Start
1978-02-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
41
Fiscal Year
2014
Total Cost
$306,727
Indirect Cost
$100,177
Name
Loma Linda University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
009656273
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
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
Longo, Lawrence D; Goyal, Ravi (2013) Cerebral artery signal transduction mechanisms: developmental changes in dynamics and Ca2+ sensitivity. Curr Vasc Pharmacol 11:655-711
Papamatheakis, Demosthenes G; Blood, Arlin B; Kim, Joon H et al. (2013) Antenatal hypoxia and pulmonary vascular function and remodeling. Curr Vasc Pharmacol 11:616-40
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; Henderson, David A; Chu, Nina et al. (2012) Ovine middle cerebral artery characterization and quantification of ultrastructure and other features: changes with development. Am J Physiol Regul Integr Comp Physiol 302:R433-45
Hartman, Richard E; Kamper, Joel E; Goyal, Ravi et al. (2012) Motor and cognitive deficits in mice bred to have low or high blood pressure. Physiol Behav 105:1092-7
Goyal, Ravi; Papamatheakis, Demosthenes G; Loftin, Matthew et al. (2011) Long-term maternal hypoxia: the role of extracellular Ca2+ entry during serotonin-mediated contractility in fetal ovine pulmonary arteries. Reprod Sci 18:948-62
Papamatheakis, Demosthenes G; Vemulakonda, Srilakshmi; Blood, Quintin et al. (2011) Preservation of serotonin-mediated contractility in adult sheep pulmonary arteries following long-term high-altitude hypoxia. High Alt Med Biol 12:253-64
Zavorsky, Gerald S; Longo, Lawrence D (2011) Exercise guidelines in pregnancy: new perspectives. Sports Med 41:345-60

Showing the most recent 10 out of 94 publications