In vivo Adenoviral Gene Transfer of CGRP and Related Peptides to the Rat and Mouse

Calcitonin gene-related peptide (CGRP) and adrenomedullin (ADM) play an important role in maintaining low pulmonary vascular resistance (PVR) and may be involved in modulating the pulmonary vascular response to chronic hypoxia. Adenoviral vectors encoding prepro-CGRP (AdRSVCGRP) and ADM (AdRSVADM) were used to examine the effects of in vivo gene transfer of the peptides to the lung on increases in PVR, right ventricular mass, and pulmonary vascular remodelling that occurs in chronic hypoxia in the mouse. Intratracheal administration of AdRSVCGRP or AdRSVADM, followed by 16 days of chronic hypoxia (FIO2 0.10), increased lung CGRP and ADM levels, respectively. The increase in pulmonary arterial pressure (PAP), PVR, right ventricular mass, and pulmonary vascular remodeling in response to chronic hypoxia was attenuated in animals overexpressing prepro-CGRP or ADM whereas systemic arterial pressure was not altered. In chronically hypoxic mice, increases in PAP in response to i.v. injections of angiotensin II and endothelin-1 were attenuated following in vivo gene transfer. These data show that in vivo transfer of the CGRP or ADM gene to the lung attenuates the increase in PVR and right ventricular mass, pulmonary vascular remodeling, and responsiveness in chronically hypoxic mice with little effect on the systemic circulation. In order to study the roles of RAMP 1, 2, and 3 in mediating responses to CGRP and related peptides in the pulmonary and systemic vascular beds, gene transfer of adenovirus vectors encoding CRLR and RAMP 1, 2, or 3 were delivered to the lung and/or hindlimb of the mouse. Transfection of CRLR and RAMP 2 to the pulmonary and hindlimb vascular beds of the mouse resulted in enhanced vasodilator responses to ADM, but not CGRP

Upregulation of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) in wall of ruptured human cerebral aneurysms: preliminary results

BACKGROUND AND PURPOSE: Cyclooxygenase-2 (COX-2) and Microsomal Prostaglandin E2 Synthase-1 (mPGES-1) catalyze isomerization of the cyclooxygenase product PGH2 into PGE2. Deletion of COX-2/mPGES-1 suppresses carotid artery atherogenesis and angiotensin II-induced aortic aneurysms formation, and attenuates neointimal hyperplasia after vascular injury in mice. The upregulation of COX-2/mPGES-1 in the wall of ruptured human cerebral aneurysms is not known. METHODS: Ten patients with intracranial aneurysms (5 ruptured and 5 nonruptured) underwent microsurgical clipping. During the procedure, a segment of the aneurysm dome was resected and immunostained with monoclonal antibodies for COX-1, COX-2, and mPGES-1. A segment of the superficial temporal artery was also removed and immunostained with monoclonal antibodies for COX-1, COX-2, and mPGES-1. RESULTS: All 10 aneurysm tissues stained positive for mPGES-1 monoclonal antibody. Expression of mPGES-1 was more abundant in ruptured aneurysm tissue than in nonruptured aneurysms, based on a semiquantitative grading. None of the superficial temporal artery specimens expressed mPGES-1. COX-2 was upregulated in the same distribution as was mPGES-1. COX-1 was present constitutively in all tissues. CONCLUSIONS: COX-2/mPGES-1 are expressed in the wall of human cerebral aneurysms and more abundantly so in ruptured aneurysms than in nonruptured. We speculate that the protective effect of aspirin against rupture of cerebral aneurysms may be mediated in part by inhibition of COX-2/mPGES-1

Restoration of Endothelium-dependent Relaxation by Dietary Treatment of Atherosclerosis Rapid Publication

Atherosclerosis results in impaired relaxation to acetylcholine, thrombin, and the calcium ionophore A23187, all agents that require the presence of endothelium. We now report that dietary treatment of atherosclerosis in monkeys not only produces morphological improvement of the atherosclerotic lesion but restores endothelium-dependent vascular relaxation to normal.]Because the intima remains thickened after regression of atherosclerosis, these studies suggest that intimal thickening which is present in both atherosclerotic vessels and after regression of atherosclerosis does not prevent the endothelium-derived relaxing factor from reaching the underlying vascular smooth muscle

Examination of the predictive validity of preschool early literacy skills

Abstract. The predictive validity of early literacy skills of children among preschool is relatively unknown. The purpose of this longitudinal study was to provide this examination. From a sample of preschoolers, longitudinal data were available for 143 of the children in kindergarten and for 116 of them through the end of first grade. Preschool children were assessed in the fall, winter, and spring with Early Literacy Individual Growth and Development Indicators (EL-IGDIs). In the fall, winter, and spring of kindergarten, literacy skills were assessed and curriculum-based measurement data in reading were collected in the spring of kindergarten and first grade. Results showed significant increases in mean EL-IGDI scores. In most instances, preschool administrations of the EL-IGDIs were moderately correlated with kindergarten measures of alphabetic principle and phonological awareness. Preschool EL-IGDIs were found to be significantly predictive of later outcomes in oral reading fluency both at the end of kindergarten and at the end of first grade. The diagnostic utility of these measures was found to be strong. Implications for practice are discussed

Abstract 10: Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice in vivo

Background and Purpose: Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor γ (PPARγ) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARγ promote atherosclerosis and vascular dysfunction. In this study, the role of PPARγ in aneurysm formation and rupture was tested. Methods: Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPARγ antagonist GW9662 or the PPARγ agonist pioglitazone, (2) mice carrying dominant-negative PPARγ mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Results: Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant-negative endothelial-specific PPARγ did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARγ resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARγ, but not dominant-negative endothelial-specific PPARγ, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P<0.05). Conclusions: Endogenous PPARγ, specifically smooth muscle PPARγ, plays an important role in protecting from formation and rupture of experimental cerebral aneurysms in mice

Early change in ferumoxytol-enhanced magnetic resonance imaging signal suggests unstable human cerebral aneurysm: A pilot study

Background and Purpose: The clinical significance of early (ie, within the first 24 hours) uptake of ferumoxytol by macrophages in the wall of human cerebral aneurysms is not clear. The purpose of this study was to determine whether early uptake of ferumoxytol suggests unstable cerebral aneurysm. Methods: Thirty unruptured aneurysms in 22 patients were imaged with magnetic resonance imaging 24 hours after infusion of ferumoxytol. Eighteen aneurysms were also imaged 72 hours after infusion of ferumoxytol. Aneurysm dome tissue was collected from 4 patients with early magnetic resonance imaging signal changes, 5 patients with late signal changes, and 5 other patients with ruptured aneurysms. The tissue was immunostained for expression of cyclooxygenase-1, cyclooxygenase-2, microsomal prostaglandin E2 synthase-1, and macrophages. Results: In 23% (7/30) of aneurysms, there was pronounced early uptake of ferumoxytol. Four aneurysms were clipped. The remaining 3 aneurysms were managed conservatively; all 3 ruptured within 6 months. In 53% (16 of 30) of aneurysms, there was pronounced uptake of ferumoxytol at 72 hours. Eight aneurysms were surgically clipped, and 8 were managed conservatively; none ruptured or increased in size after 6 months. Expression of cyclooxygenase-2, microsomal prostaglandin E2 synthase-1, and macrophages was similar in unruptured aneurysms with early uptake of ferumoxytol and ruptured aneurysms. Expression of these inflammatory molecules was significantly higher in aneurysms with early uptake of ferumoxytol versus aneurysms with late uptake. Conclusions: Uptake of ferumoxytol in aneurysm walls within the first 24 hours strongly suggests aneurysm instability and probability of rupture within 6 months, and may warrant urgent intervention. © 2012 American Heart Association, Inc