• The Role of Uridine Adenosine Tetraphosphate in the Vascular System

      Matsumoto, Takayuki; Tostes, Rita C.; Webb, R. Clinton; Department of Physiology (2011-11-1)
      The endothelium plays a pivotal role in vascular homeostasis, and endothelial dysfunction is a major feature of cardiovascular diseases, such as arterial hypertension, atherosclerosis, and diabetes. Recently, uridine adenosine tetraphosphate (Up4A) has been identified as a novel and potent endothelium-derived contracting factor (EDCF). Up4A structurally contains both purine and pyrimidine moieties, which activate purinergic receptors. There is an accumulating body of evidence to show that Up4A modulates vascular function by actions on endothelial and smooth muscle cells. In this paper, we discuss the effects of Up4A on vascular function and a potential role for Up4A in cardiovascular diseases.
    • Strategies and methods to study sex differences in cardiovascular structure and function: a guide for basic scientists

      Miller, Virginia M; Kaplan, Jay R; Schork, Nicholas J; Ouyang, Pamela; Berga, Sarah L; Wenger, Nanette K; Shaw, Leslee J; Webb, R. Clinton; Mallampalli, Monica; Steiner, Meir; et al. (2011-12-12)
      Background: Cardiovascular disease remains the primary cause of death worldwide. In the US, deaths due to cardiovascular disease for women exceed those of men. While cultural and psychosocial factors such as education, economic status, marital status and access to healthcare contribute to sex differences in adverse outcomes, physiological and molecular bases of differences between women and men that contribute to development of cardiovascular disease and response to therapy remain underexplored.
    • Thyroidal dysfunction and environmental chemicals--potential impact on brain development.

      Porterfield, S P; Department of Physiology (2000-10-23)
      Certain polyhalogenated aromatic hydrocarbons such as polychlorinated biphenyls (PCBs) and dibenzo-p-dioxins (dioxins, 2,3,7, 8-tetrachlorodibenzo-p-dioxin) have been shown to have neurotoxic effects and to alter thyroid function during critical periods of thyroid hormone-dependent brain development. This has led to the suggestion that some of the neurotoxic effects of these compounds could be mediated through the thyroid system. Thyroid hormones are essential for normal brain development during a critical period beginning in utero and extending through the first 2 years postpartum. They regulate neuronal proliferation, migration, and differentiation in discrete regions of the brain during definitive time periods. Even transient disruption of this normal pattern can impair brain development. Thyroid hormones are necessary for normal cytoskeletal assembly and stability and the cytoskeletal system is essential for migration and neuronal outgrowth. In addition, they regulate development of cholinergic and dopaminergic systems serving the cerebral cortex and hippocampus. Animals perinatally exposed to certain environmental organohalogens such as many of the PCBs and dioxins have abnormal thyroid function and neurologic impairment. Although there are both species and congener variabilities, most reports show exposure results in thyroid enlargement and reduced serum T(4) levels with normal T(3) levels. Initial research concentrated on studying the direct actions of xenobiotics on the thyroid; however, some of these compounds bear a structural resemblance to the natural thyroid hormones and have high affinity with thyroid hormone-binding proteins such as transthyretin. These compounds could act as agonists or antagonists for receptors of the thyroid/steroid/retinoic acid superfamily. These structurally similar organohalogens could act at multiple points to alter thyroid hormone action. The similarity of the neurologic impairment seen in thyroid disorders to that seen following PCB or dioxin exposure suggests that one mechanism of neurotoxicity of these compounds could involve interaction with the thyroid system.
    • Vascular Protection by Angiotensin Receptor Antagonism Involves Differential VEGF Expression in Both Hemispheres after Experimental Stroke

      Guan, Weihua; Somanath, Payaningal R.; Kozak, Anna; Goc, Anna; El-Remessy, Azza B.; Ergul, Adviye; Johnson, Maribeth H.; Alhusban, Ahmed; Soliman, Sahar; Fagan, Susan C.; et al. (2011-09-1)
      We identified that the angiotensin receptor antagonist, candesartan, has profound neurovascular protective properties when administered after ischemic stroke and was associated with a proangiogenic state at least partly explained by vascular endothelial growth factor A (VEGFA). However, the spatial distribution of vascular endothelial growth factor (VEGF) isoforms and their receptors remained unknown. Protein analysis identified a significant increase in vascular endothelial grow factor B (VEGFB) in the cerebrospinal fluid (CSF) and the ischemic hemispheres (with increased VEGF receptor 1 activation) of treated animals (p<0.05) which was co-occurring with an increase in protein kinase B (Akt) phosphorylation (p<0.05). An increase in VEGFA protein in the contralesional hemisphere corresponded to a significant increase in vascular density at seven days (p<0.01) after stroke onset
    • Vulnerability of the developing brain to thyroid abnormalities: environmental insults to the thyroid system.

      Porterfield, S P; Department of Physiology (1994-11-23)
      Neurologic development follows orderly patterns that can be severely disturbed when thyroid hormones are deficient or excessive. Should this occur at appropriate development periods, irreversible neurologic damage can result. The nature of the deficits depends upon the specific development period and the severity of the thyroid disturbance. PCBs and dioxins are structurally similar to the thyroid hormones. Their binding characteristics are similar to those of thyroid hormones and all three groups bind to the cytosolic Ah receptor, the thyroid hormone receptor and the serum thyroid hormone binding protein transthyretin. Depending upon the dose of toxin and the congener used, the toxins either decrease or mimic the biological action of the thyroid hormones. Either effect, if occurring during brain development, can have disastrous consequences. Children and animals exposed to PCBs or dioxins in utero and/or as infants can exhibit varying degrees of behavioral disorders. These disorders resemble those seen in children exposed to thyroid hormone deficiencies in utero and/or in infancy. The mechanism of developmental neurotoxicity of PCBs and dioxins is not known but data suggest it could be partially or entirely mediated by alterations in availability and action of thyroid hormones during neurological development. It is possible that transient exposure of the mother to doses of toxins presently considered nontoxic to the mother could have an impact upon fetal or perinatal neurological development. If the toxins act via their effect on thyroid hormone action, it is possible that doses of toxins that would normally not alter fetal development, could become deleterious if superimposed on a pre-existing maternal/or fetal thyroid disorder.