In this renewal application, Dr. Pearce proposes a series of studies that focus on the mechanisms potentially responsible for the observed age-related differences in late fetal/neonatal and adult cerebral artery reactivity to contractile amines. Based on the general hypothesis that maturation modulates cerebrovascular reactivity by enhancing IP3-dependent, and depressing IP3-independent mechanisms of pharmacomechanical coupling, Dr. Pearce proposes three multifaceted specific aims.
These specific aims i nclude: 1) to determine if agonist-stimulation produces less intracellular calcium release and greater entry of extracellular calcium in cerebral vessels from immature vs. mature sheep, 2) to determine if attenuated IP3 receptor GAIN is the main factor responsible for depressed cerebrovascular reactivity to IP3 observed in neonatal sheep, and 3) to determine if IP3-independent agonist-induced shifts in myofilament Ca2+ sensitivity are greater in cerebral arteries from immature vs. mature sheep. To address these aims, Dr. Pearce proposes a series of mechanistic studies utilizing in vitro vessel contraction techniques, cytosolic calcium studies, sarcoplasmic reticulum calcium mass determinations, IP3-receptor radioligand binding studies, G-protein activation and inhibition protocols, PKC inhibition studies, and MLC phosphorylation assays. To evaluate the influence of differences in arterial size and type, all of these experiments will be conducted in segments obtained from both common carotid and middle cerebral arteries.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL054120-04
Application #
2472591
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Project Start
1995-04-01
Project End
2002-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Loma Linda University
Department
Biology
Type
Schools of Medicine
DUNS #
City
Loma Linda
State
CA
Country
United States
Zip Code
92350
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
Pearce, William J (2014) The fetal cerebral circulation: three decades of exploration by the LLU Center for Perinatal Biology. Adv Exp Med Biol 814:177-91
Durrant, Lara M; Khorram, Omid; Buchholz, John N et al. (2014) Maternal food restriction modulates cerebrovascular structure and contractility in adult rat offspring: effects of metyrapone. Am J Physiol Regul Integr Comp Physiol 306:R401-10
Adeoye, Olayemi O; Bouthors, Vincent; Hubbell, Margaret C et al. (2014) VEGF receptors mediate hypoxic remodeling of adult ovine carotid arteries. J Appl Physiol (1985) 117:777-87
Pearce, William J; Khorram, Omid (2013) Maturation and differentiation of the fetal vasculature. Clin Obstet Gynecol 56:537-48
Adeoye, Olayemi O; Butler, Stacy M; Hubbell, Margaret C et al. (2013) Contribution of increased VEGF receptors to hypoxic changes in fetal ovine carotid artery contractile proteins. Am J Physiol Cell Physiol 304:C656-65
Hubbell, Margaret C; Semotiuk, Andrew J; Thorpe, Richard B et al. (2012) Chronic hypoxia and VEGF differentially modulate abundance and organization of myosin heavy chain isoforms in fetal and adult ovine arteries. Am J Physiol Cell Physiol 303:C1090-103
Pearce, William J; Butler, Stacy M; Abrassart, Jenna M et al. (2011) Fetal cerebral oxygenation: the homeostatic role of vascular adaptations to hypoxic stress. Adv Exp Med Biol 701:225-32
Butler, Stacy M; Abrassart, Jenna M; Hubbell, Margaret C et al. (2011) Contributions of VEGF to age-dependent transmural gradients in contractile protein expression in ovine carotid arteries. Am J Physiol Cell Physiol 301:C653-66
Khorram, O; Han, G; Bagherpour, R et al. (2010) Effect of maternal undernutrition on vascular expression of micro and messenger RNA in newborn and aging offspring. Am J Physiol Regul Integr Comp Physiol 298:R1366-74

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