DOCSLIB.ORG

Mechanisms of Disease: Pulmonary Arterial Hypertension Ralph T

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Mechanisms of Disease: Pulmonary Arterial Hypertension Ralph T REVIEWS Mechanisms of disease: pulmonary arterial hypertension Ralph T. Schermuly, Hossein A. Ghofrani, Martin R. Wilkins and Friedrich Grimminger Abstract | Our understanding of, and approach to, pulmonary arterial hypertension has undergone a paradigm shift in the past decade. Once a condition thought to be dominated by increased vasoconstrictor tone and thrombosis, pulmonary arterial hypertension is now seen as a vasculopathy in which structural changes driven by excessive vascular cell growth and inflammation, with recruitment and infiltration of circulating cells, play a major role. Perturbations of a number of molecular mechanisms have been described, including pathways involving growth factors, cytokines, metabolic signaling, elastases, and proteases, that may underlie the pathogenesis of the disease. Elucidating their contribution to the pathophysiology of pulmonary arterial hypertension could offer new drug targets. The role of progenitor cells in vascular repair is also under active investigation. The right ventricular response to increased pressure load is recognized as critical to survival and the molecular mechanisms involved are attracting increasing interest. The challenge now is to integrate this new knowledge and explore how it can be used to categorize patients by molecular phenotype and tailor treatment more effectively. Schermuly, R. T. et al. Nat. Rev. Cardiol. 8, 443–455 (2011); published online 21 June 2011; doi:10.1038/nrcardio.2011.87 Introduction Pulmonary hypertension is a progressive disease of various receptor superfamily and, more rarely, in activin receptor- origins that is associated with a poor prognosis and results like kinase type 1 (ALK-1; also called ACVRL1) have been in right heart dysfunction. In all its variant presentations, identified as underlying mechanisms. Drug-induced and this disease is estimated to affect up to 100 million people toxin-induced forms of PAH are included in group 1.3, and worldwide.1 According to the current classification of group 1.4 comprises PAH associated with identified diseases pulmo nary hypertension, which was agreed upon at the (for example, HIV and schistosomiasis infections). Persistent 4th World Symposium on Pulmonary Hypertension in pulmonary hypertension of the newborn is included in 2008, five categories of chronic pulmonary hypertension group 1.5, and patients with pulmonary veno-occlusive exist (Box 1).2 disease and/or pulmonary capillary hemangiomatosis are In this Review, we focus on molecular mechanisms classified as being in group 1'.1,3–5 involved in the pathogenesis of group 1, pulmonary arterial In this article, we highlight findings from patients with Max-Planck-Institute hypertension (PAH), which includes a variety of diseases PAH. However, we also discuss preclinical data from a for Heart and Lung that share several pathophysiological, histological, and number of animal models of pulmonary hypertension. Research, prognostic features. Although rare, idiopathic PAH (IPAH; Notably, although the existing animal models inform on Parkstrasse 1, 61231 Bad Nauheim, group 1.1) defines the group and is a disease in which there certain aspects of PAH, no animal model of pulmonary Germany is neither a family history of, nor an identified risk factor for, hypertension recapitulates the human condition. For (R. T. Schermuly). University Hospital PAH. In heritable PAH (group 1.2; formerly known as famil- example, mice exposed to hypoxia develop pulmonary Giessen and Marburg, ial PAH), loss-of-function mutations in the transforming hypertension and are widely used as a disease model, but University of Giessen growth factor β/bone morphogenetic protein (TGF-β/BMP) although they display certain features in common with Lung Center, Klinikstrasse 36, PAH, they are more closely related to group 3 pulmonary 35392 Giessen, Competing interests hypertension. Rats treated with the toxin monocrotaline, Germany R. T. Schermuly declares associations with Actelion, Bayer another frequently used model of pulmonary hypertension, (H. A. Ghofrani, Healthcare, Ergonex, Excellence Cluster Cardiopulmonary F. Grimminger). Centre may exhibit direct damage to the liver, kidneys, and heart, for Pharmacology and System, German Research Foundation, Gilead, GlaxoSmithKline, in addition to the pulmonary vasculature. For an in-depth Therapeutics, Division Lilly, Novartis, Pfizer, Solvay Pharmaceuticals, and the University of Experimental of Giessen and Marburg Lung Center. H. A. Ghofrani declares discussion of the merits and limitations of the different Medicine, Imperial associations with Bayer Healthcare, Ergonex, Excellence Cluster animal models of pulmonary hypertension and their rele- College London, Cardiopulmonary System, German Research Foundation, Hammersmith Hospital, GlaxoSmithKline, Novartis, Pfizer, and the University of Giessen vance to human PAH, the reader is referred to an article by Du Cane Road, 6 and Marburg Lung Center. M. R. Wilkins declares associations Stenmark et al. London W12 0NN, UK with Bayer Healthcare, Biomarin, GlaxoSmithKline, and Pfizer. (M. R. Wilkins). F. Grimminger declares associations with Actelion, Bayer Pathways of disease Correspondence to: Healthcare, Encysive, Excellence Cluster Cardiopulmonary The subcategories of PAH differ in their under lying causes. R. T. Schermuly System, German Research Foundation, GlaxoSmithKline, ralph.schermuly@ Novartis, Parexel International GmbH, Pfizer, and the University However, all are characterized by excessive pulmonary innere.med. of Giessen and Marburg Lung Center. vasoconstriction and abnormal vascular remodeling uni-giessen.de NATURE REVIEWS | CARDIOLOGY VOLUME 8 | AUGUST 2011 | 443 © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS 9 Key points unique plexiform lesions. Vascular smooth muscle cell (SMC) proliferation is a prominent feature of PAH. These ■ Pulmonary hypertension is a progressive disease of various origins, which has a poor prognosis and affects, in its different forms, more than 100 million structural changes suggest a switch from a quiescent state people worldwide to a proliferative, apoptosis-resistant cellular phenotype. Lung vascular remodeling can be associated with chronic ■ Pulmonary arterial hypertension (PAH) is now considered to be a vasculopathy in which structural changes driven by excessive vascular cell growth and inflammatory events and recruitment of progenitor cell inflammation have a major role types, which might fuel proliferative changes (for example, ■ A number of proproliferative signaling pathways involving growth factors, in circulating fibrocytes and mesenchymal progenitor 10 cytokines, metabolic signaling, and elastases and proteases have been cells) or which might have an antiproliferative effect identified in the pathophysiology of PAH and thus offer a prospective therapeutic intervention (for 11 ■ Clinical studies with tyrosine kinase inhibitors, serotonin antagonists, and example, endothelial progenitor cells). soluble guanylate cyclase stimulators are underway in patients with PAH ■ The benefits of progenitor cells for vascular repair in PAH are under active Imbalance in vasoactive mediators investigation In patients with PAH, the generation of vasodilatory medi- 12,13 ■ The right ventricular response to increased pressure load is recognized as ators, in particular prostaglandin I2, is reduced. Reduced critical to survival in patients with PAH, and strategies for preserving myocardial levels of the vasodilatory and antiproliferative nitric oxide function are increasingly attracting interest (NO; generated via NO synthases), and cyclic guanosine monophosphate (the second messenger downstream of NO) are also well described in pulmonary vascular disease, Box 1 | Current classification of pulmonary hypertension including PAH.14,15 Increased levels of asymmetric dimethyl- As agreed at the 4th World Symposium on Pulmonary arginine (an endogenous inhibitor of NO synthase) might Hypertension in Dana Point, CA, USA, in 2008, pulmonary also have a functional role in PAH (Figure 2).16,17 hypertension is now classified into five groups:5 In addition to reduced generation of vasodilatory Group 1—Pulmonary arterial hypertension medi ators in patients with PAH, levels of the potent vaso constrictors thromboxane and endothelin 1 are ■ Group 1.1—Idiopathic pulmonary arterial hypertension increased.12,13 Moreover, 5-hydroxytryptamine (5-HT) Group 1.2—Heritable pulmonary arterial hypertension ■ causes vasoconstriction, and abnormalities in endothelial (formerly known as familial pulmonary arterial hypertension) cell–SMC cross-talk have been observed in humans with IPAH and a mouse model of hypoxia-induced pulmonary ■ Group 1.3—Drug-induced and toxin-induced forms of pulmonary arterial hypertension hypertension, with enhanced endothelial 5-HT production, transport, and paracrine activity in adjacent pulmonary ■ Group 1.4—Pulmonary arterial hypertension 18,19 associated with identified diseases (for example, HIV vascular SMCs. Certain forms of drug-induced or toxin- and schistosomiasis infections) induced PAH (group 1.3) also involve the 5-HT pathway. Fenfluramine and aminorex, anorexigenic drugs associ- ■ Group 1.5—Persistent pulmonary hypertension of the newborn ated with an increased risk of PAH, are both 5-HT trans- porter substrates and increase extracellular concentrations Group 1'—Pulmonary veno-occlusive disease and/or of 5-HT.20 pulmonary capillary hemangiomatosis Abnormalities in both K+ channels and Ca2+ channels Group 2—Pulmonary hypertension
Load more

Recommended publications
  • Regulation of Intestinal Blood Flow
    Journal of Surgical Research 93, 182–196 (2000) doi:10.1006/jsre.2000.5862, available online at http://www.idealibrary.com on RESEARCH REVIEW Regulation of Intestinal Blood Flow Paul J. Matheson, Ph.D.,*,†,1 Mark A. Wilson, M.D., Ph.D.,*,†,‡ and R. Neal Garrison, M.D.*,†,‡ *Center for Excellence in Applied Microcirculatory Research and ‡Department of Surgery, University of Louisville, Louisville, Kentucky 40292; and †Louisville Veterans Affairs Medical Center, Louisville, Kentucky 40206 Submitted for publication July 29, 1999 arteries is typically 20–25% of cardiac output in the The gastrointestinal system anatomically is posi- unfed state [2]. There is extensive overlap or collateral tioned to perform two distinct functions: to digest and circulation in the distal vascular distributions of these absorb ingested nutrients and to sustain barrier func- arteries. During nutrient absorption, blood flow in each tion to prevent transepithelial migration of bacteria of these arteries is increased sequentially as the diges- and antigens. Alterations in these basic functions con- tive chyme passes over the mucosal surface supplied by tribute to a variety of clinical scenarios. These pri- mary functions intrinsically require splanchnic blood the particular arteries [3]. Following nutrient absorp- flow at both the macrovascular and microvascular lev- tion, the blood flow to each segment returns to baseline els of perfusion. Therefore, a greater understanding of levels as the chyme moves past that region of the the mechanisms that regulate intestinal vascular per- digestive tract [4, 5]. This postprandial increase in fusion in the normal state and during pathophysiolog- blood flow is independent of organ distention and is ical conditions would be beneficial.
    [Show full text]
  • Modeling Vascular Homeostasis and Improving Data Filtering Methods for Model Calibration
    Modeling Vascular Homeostasis and Improving Data Filtering Methods for Model Calibration by Jiacheng Wu A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Engineering − Mechanical Engineering and the Designated Emphasis in Computational Science and Engineering in the Graduate Division of the University of California, Berkeley Committee in charge: Professor Shawn C. Shadden, Chair Professor Grace D. O'Connell Professor Peter L. Bartlett Spring 2019 Modeling Vascular Homeostasis and Improving Data Filtering Methods for Model Calibration Copyright 2019 by Jiacheng Wu 1 Abstract Modeling Vascular Homeostasis and Improving Data Filtering Methods for Model Calibration by Jiacheng Wu Doctor of Philosophy in Engineering − Mechanical Engineering and the Designated Emphasis in Computational Science and Engineering University of California, Berkeley Professor Shawn C. Shadden, Chair Vascular homeostasis is the preferred state that blood vessels try to maintain against external mechanical and chemical stimuli. The vascular adaptive behavior around the homeostatic state is closely related to cardiovascular disease progressions such as arterial aneurysms. In this work, we develop a multi-physics computational framework that couples vascular growth & remodeling (G&R), wall mechanics and hemodynamics to describe the overall vascular adaptive behavior. The coupled simulation is implemented in patient-specific geometries to predict aneurysm progression. Lyapunov stability analysis of the governing
    [Show full text]
  • Tracheal Suctioning Improves Gas Exchange but Not Hemodynamics in Asphyxiated Lambs with Meconium Aspiration
    nature publishing group Translational Investigation Articles Tracheal suctioning improves gas exchange but not hemodynamics in asphyxiated lambs with meconium aspiration Satyan Lakshminrusimha1, Bobby Mathew1, Jayasree Nair1, Sylvia F. Gugino1,2, Carmon Koenigsknecht1, Munmun Rawat1, Lori Nielsen1 and Daniel D. Swartz1,2 BACKGROUND: Current neonatal resuscitation guidelines suctioning for vigorous infants (9). Approximately 20–30% recommend tracheal suctioning of nonvigorous neonates of infants born through MSAF are depressed at birth with an born through meconium-stained amniotic fluid. Apgar score of 6 or less at 1 min of age (10). Babies exposed to METHODS: We evaluated the effect of tracheal suctioning at MSAF who have respiratory depression at birth have a higher birth in 29 lambs with asphyxia induced by cord occlusion and incidence of MAS (11). If a baby is born through MSAF, has meconium aspiration during gasping. depressed respirations, decreased muscle tone, and/or a heart RESULTS: Tracheal suctioning at birth (n = 15) decreased rate below 100/min, intubation and direct suctioning of the amount of meconium in distal airways (53 ± 29 particles/mm2 trachea soon after delivery is indicated before breaths have lung area) compared to no suction (499 ± 109 particles/mm2; occurred. There are no randomized, clinical, or translational n = 14; P < 0.001). Three lambs in the suction group had car- studies evaluating the effect of tracheal suctioning on hemody- diac arrest during suctioning, requiring chest compressions namics and gas exchange with perinatal meconium aspiration and epinephrine. Onset of ventilation was delayed in the suc- and asphyxia-induced depression. tion group (146 ± 11 vs. 47 ± 3 s in no-suction group; P = 0.005).
    [Show full text]
  • Clinical Practice Guideline: Red Blood Cell Transfusion in Adult Trauma and Critical Care*
    Special Article Clinical practice guideline: Red blood cell transfusion in adult trauma and critical care* Lena M. Napolitano, MD; Stanley Kurek, DO; Fred A. Luchette, MD; Howard L. Corwin, MD; Philip S. Barie, MD; Samuel A. Tisherman, MD; Paul C. Hebert, MD, MHSc; Gary L. Anderson, DO; Michael R. Bard, MD; William Bromberg, MD; William C. Chiu, MD; Mark D. Cipolle, MD; PhD; Keith D. Clancy, MD; Lawrence Diebel, MD; William S. Hoff, MD; K. Michael Hughes, DO; Imtiaz Munshi, MD; Donna Nayduch, RN, MSN, ACNP; Rovinder Sandhu, MD; Jay A. Yelon, MD; for the American College of Critical Care Medicine of the Society of Critical Care Medicine and the Eastern Association for the Surgery of Trauma Practice Management Workgroup Objective: To develop a clinical practice guideline for red blood proved by the EAST Board of Directors, the Board of Regents of the cell transfusion in adult trauma and critical care. ACCM and the Council of SCCM. Design: Meetings, teleconferences and electronic-based com- Results: Key recommendations are listed by category, including munication to achieve grading of the published evidence, discus- (A) Indications for RBC transfusion in the general critically ill patient; sion and consensus among the entire committee members. (B) RBC transfusion in sepsis; (C) RBC transfusion in patients at risk Methods: This practice management guideline was developed by for or with acute lung injury and acute respiratory distress syn- a joint taskforce of EAST (Eastern Association for Surgery of Trauma) drome; (D) RBC transfusion in patients with neurologic injury and the American College of Critical Care Medicine (ACCM) of the and diseases; (E) RBC transfusion risks; (F) Alternatives to RBC Society of Critical Care Medicine (SCCM).
    [Show full text]
  • Inhaled Nitric Oxide and Intravenous Magnesium Sulphate for The
    Original Article Singapore Med J 2010; 51(2) : 144 Inhaled nitric oxide and intravenous magnesium sulphate for the treatment of persistent pulmonary hypertension of the newborn Boo N Y, Rohana J, Yong S C, Bilkis A Z, Yong-Junina F ABSTRACT ated with a better outcome than those who Introduction: The aim of this study was to were administered MgSO4 following a failed iNO compare the response and survival rates of term therapy. infants with persistent pulmonary hypertension of the newborn (PPHN) on high frequency oscil- Keywords: inhaled nitric oxide, intravenous latory ventilation (HFOV) treated with either magnesium sulphate, PPHN inhaled nitric oxide (iNO) or intravenous magne- Singapore Med J 2010; 51(2): 144-150 sium sulphate (MgSO4). INTRODUCTION Methods: This was a randomised controlled study. Persistent pulmonary hypertension of the newborn The inclusion criteria were infants with respira- (PPHN) is a complex disorder that is associated tory distress, oxygen index equal to or greater with a wide array of cardiopulmonary diseases and is than 25 despite HFOV support, and echocardio- characterised by marked pulmonary hypertension and graphic evidence of PPHN. Infants in the MgSO4 altered vasoreactivity, leading to the right-to-left shunting group (n is 13) were loaded with MgSO4 200 mg/kg of blood across the patent ductus arteriosus and/or Department of infused over half an hour, followed by continuous foramen ovale. This extrapulmonary shunting associated Paediatics, infusion at 50–150 mg/kg/hour to attain a serum Universiti with high pulmonary vascular resistance causes critical Kebangsaan magnesium level of 5.0–7.0 mmol/L.
    [Show full text]
  • Cardiovascular Changes in the Lingcod (Ophiodon Elongatus) Following Adrenergic and Cholinergic Drug Infusions
    y. exp. Biol. (1981), 91. 293-3OS 293 With 5 figures in Great Britain CARDIOVASCULAR CHANGES IN THE LINGCOD (OPHIODON ELONGATUS) FOLLOWING ADRENERGIC AND CHOLINERGIC DRUG INFUSIONS BY A. P. FARRELL* Department of Zoology, University of British Columbia, Vancouver, Canada (Received 25 June 1980) SUMMARY Adrenergic and cholinergic agonists were infused into the ventral aorta to evoke gill vasoactivity in the lingcod, Ophiodon elongatus. Arterial blood pres- sures were changed, and cardiac output and stroke volume were increased. As a. consequence both the pressure and flow profiles across the gill were altered, and these changes should alter the pattern of lamellar perfusion. The changes in cardiac function were apparently reflexly mediated. INTRODUCTION The control of lamellar perfusion patterns in fish is not fully understood. Neural and humoral mediated vasoactivities are presumeably important in the control since many investigations have indicated that adrenergic and cholinergic vascular receptors are present in the gills (Wood, 1974, 1975, 1977; Smith, 1977; Payan & Girard, 1977; Dunel & Laurent, 1977). Nevertheless, unequivocal evidence of lamellar innervation or vasoactivity is lacking. Thus neural or humoral control of lamellar arterioles has still to be unequivocally demonstrated. In view of this, it is possible that changes in the pressure and flow profiles across the gill cause important, passive changes in lamellar perfusion. The lamellar blood space and the number of lamellae perfused are pressure and flow dependent in Ophiodon elongatus (Farrell, Daxboeck & Randall, 1979; Farrell et al., 1980) and in Ictalurus punctatus (Holbert, Boland & Olson, 1979). Also, Opdyke, Holcombe & Wilde (1979) concluded for Squalus acanthias that the reduced gill resis- tance associated with an increase in flow was due to passive changes in the branchial vasculature.
    [Show full text]
  • Inomax, INN-Nitric Oxide
    SCIENTIFIC DISCUSSION This module reflects the initial scientific discussion for the approval of INOmax. For information on changes after approval please refer to module 8. 1. Introduction Persistent pulmonary hypertension of the new-born (PPHN) is a disorder of the transition from foetal to extra-uterine life, a clinical syndrome characterised by persistence of elevated pulmonary vascular resistance producing right-to-left shunting of deoxygenated blood across the still patent foramen ovale and/or ductus arteriosus as well as systemic hypoxemia. PPHN may be idiopathic or associated with parenchyma lung disease as respiratory distress syndrome of prematurity, meconium aspiration syndrome, pneumonia and sepsis or congenital diaphragmatic hernia and pulmonary hypoplasia. Although anatomical changes such as pulmonary vascular smooth muscle hypertrophy may occur and contribute to increased pulmonary resistance, pulmonary vasoconstriction and altered vascular reactivity are central to the pathophysiology of this syndrome. PPHN is an uncommon life threatening condition (the incidence is less than 0.1% of life births and mortality up to 40%). Conventional therapy consists in hyperoxygenation through mechanical ventilation with hyperoxic gas mixtures, induced metabolic or respiratory alkalosis, deep sedation and pharmacological paralysis to reduce pulmonary vasoactivity. Intravenous vasodilators as sodium nitroprusside or tolazoline may be useful but can lead to severe systemic hypotension, which in turn aggravate the right-to-left shunt. In the most severe forms of hypoxic respiratory failure, invasive procedures of extracorporeal membrane oxygenation (ECMO) have proven efficacy in reducing mortality compared to conventional therapies. However, these techniques remain procedures of exception performed by a trained and specialised neonatology team. They require catheterisation and often ligation of the cervical great vessels (jugular vein and carotid artery) need continuous blood anticoagulation and use of blood products.
    [Show full text]
  • Effects of Hemoglobin-Based Oxygen Carriers on the Vasoactivity of the Spinotrapezius Muscle of the Rat
    Virginia Commonwealth University VCU Scholars Compass Theses and Dissertations Graduate School 2008 Effects of Hemoglobin-Based Oxygen Carriers on the Vasoactivity of the Spinotrapezius Muscle of the Rat Pete Meliagros Virginia Commonwealth University Follow this and additional works at: https://scholarscompass.vcu.edu/etd Part of the Physiology Commons © The Author Downloaded from https://scholarscompass.vcu.edu/etd/1674 This Thesis is brought to you for free and open access by the Graduate School at VCU Scholars Compass. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of VCU Scholars Compass. For more information, please contact [email protected]. EFFECTS OF HEMOGLOBIN-BASED OXYGEN CARRIERS ON VASOACTIVITY IN THE SPINOTRAPEZIUS MUSCLE OF THE RAT A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at the Medical College of Virginia Campus Virginia Commonwealth University By Pete Dennis Meliagros B.S. and B.A., University of Virginia 2006 Advisor Roland N. Pittman, Ph.D. Professor Department of Physiology and Biophysics Virginia Commonwealth University Richmond, Virginia May 2008 ii ACKNOWLEDGEMENTS I am very fortunate to have been a part of a lab with so many wonderful and brilliant individuals. By no means could I have accomplished my goals without their influence. First and foremost, I wish to express my gratitude to Dr. Roland Pittman. He was not only supportive of my goals in lab, but also my goals in life. I am forever indebted to him for all the time he spent sharing his knowledge and experience with me, no matter how busy his schedule.
    [Show full text]
  • Complementary Vasoactivity and Matrix Remodeling In
    COMPLEMENTARY VASOACTIVITY AND MATRIX REMODELING IN ARTERIES: THEORETICAL FOUNDATIONS AND PREDICTED TRENDS A Dissertation by ARTURO VALENT´IN III Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY August 2009 Major Subject: Biomedical Engineering COMPLEMENTARY VASOACTIVITY AND MATRIX REMODELING IN ARTERIES: THEORETICAL FOUNDATIONS AND PREDICTED TRENDS A Dissertation by ARTURO VALENT´IN III Submitted to the Office of Graduate Studies of Texas A&M University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Approved by: Chair of Committee, Jay D. Humphrey Committee Members, James E. Moore Jr. Christopher M. Quick Hsin-i Wu Head of Department, Gerard L. Cot´e August 2009 Major Subject: Biomedical Engineering iii ABSTRACT Complementary Vasoactivity and Matrix Remodeling in Arteries: Theoretical Foundations and Predicted Trends. (August 2009) Arturo Valent´ın III, B.S., University of South Carolina; M.S., University of South Carolina Chair of Advisory Committee: Dr. Jay D. Humphrey Arteries possess the ability to grow and remodel in response to sustained alter- ations in biomechanical loading, likely via mechanisms that are similarly involved in diverse arterial pathologies and responses to treatment. In particular, myriad exper- minental observations suggest that cell and matrix turnover within vasoaltered states enable arteries to adapt to sustained changes in mechanical stimuli. The goal herein is to show explicitly how altered smooth muscle contractility and matrix growth and remodeling work together to adapt the geometry, structure, stiffness, and function of a representative basilar artery. This work seeks to illustrate the importance of complementary vasoactivity and matrix remodeling for basilar arteries in response to sustained alterations in mechanical stimuli.
    [Show full text]
  • Article in Press
    ARTICLE IN PRESS Journal of Biomechanics 43 (2010) 1864–1869 Contents lists available at ScienceDirect Journal of Biomechanics journal homepage: www.elsevier.com/locate/jbiomech www.JBiomech.com The effects of vasoactivity and hypoxic pulmonary hypertension on extralobar pulmonary artery biomechanics Diana M. Tabima, Naomi C. Chesler n Department of Biomedical Engineering, University of Wisconsin at Madison, 2146 Engineering Centers Building, 1550 Engineering Drive, Madison, WI 53706-1609, USA article info abstract Article history: Loss of large artery compliance is an emerging novel predictor of cardiovascular mortality. Hypoxia- Accepted 19 March 2010 induced pulmonary hypertension (HPH) has been shown to decrease extralobar pulmonary artery (PA) compliance in the absence of smooth muscle cell (SMC) tone and to increase SMC tone in peripheral Keywords: PAs. We sought to determine the impact of HPH on extralobar PA tone and the impact of SMC activation Elastic modulus on extralobar PA biomechanics. To do so, C57BL6 mice were exposed to 0 (CTL) or 10 days (HPH) of Chronic hypoxia hypoxia and isolated vessel tests were performed on extralobar PAs using either a physiological saline Compliance solution (PSS), a vasoconstrictor (U46619), two vasodilators (SNP and Y27632) or calcium free medium (relaxant solution; VBRS). The vasodilators and relaxant solution had no effect on extralobar artery diameter suggesting that basal SMC tone is essentially zero in CTL conditions and does not increase with HPH. HPH caused narrowing, decreased circumferential stretch (l; po0.0001), decreased local area compliance (CA; po0.0005) and increased incremental elastic modulus (Einc; po0.05) in the normal tone state (with PSS). In both CTL and HPH conditions, SMC activation decreased Einc (po0.0005) but also increased wall thickness (po0.05) such that changes in CA with SMC constriction were minimal; only in HPH PAs was a significant decrease with SMC constriction observed (po0.05).
    [Show full text]
  • Role of Myocardial Contractions on Coronary Vasoactivity
    MCB, vol.16, supplemental 2, pp.84-86, 2019 Role of Myocardial Contractions on Coronary Vasoactivity Xiao Lu1,* and Ghassan Kassab1 California Medical Innovations Institute, San Diego, CA 92121, USA. Corresponding Author: Xiao Lu. Email: [email protected]. Keywords: Extrinsic Pressure; coronary arterioles; mechanotransduction; heart failure; myocardial contractility; tachycardia Background: Heart failure (HF) is accompanied by alteration of hemodynamic conditions, which is due to the triggers of complex reflex changes in the sympathetic, endocrine, and rennin systems [1–2]. A critical effect of HF is reduced blood flow (ischemia) in the cardiovascular system resulting from mild to severe reduction in cardiac output (CO) due to dysfunction of myocardial contractility. It is known that coronary flow is regulated by many factors, including metabolic demand, perfusion pressure, oxidative stress, etc. Vascular vasodilation and vasoconstriction change microcirculation resistance and therefore regulate coronary circulation. However, it is not clear whether myocardial contractility may affect coronary tone to regulate coronary circulation in HF, i.e., the role the extrinsic mechanics in coronary arteriole tone. It is recognized that the extrinsic compression on blood vessel wall during skeletal muscle contraction is an independent regulator of vascular tone (3-4). Myocardial contraction also leads to such compression on intra-myocardial arterioles. Therefore, we hypothesize that myocardial contractility will change the arteriole tone to regulate
    [Show full text]
  • The Vasoactivity of the Fetal Lamb Ductus Arteriosus Studied in Utero
    Pediatr. Res. 17: 331-337 (1983) The Vasoactivity of the Fetal Lamb Ductus Arteriosus Studied in Utero WILLIAM F. FRIED MAN,(^^' MORTON P. PRINTZ, STANLEY E. KIRKPATRICK, AND ED J. HOSKINS Division of Pediatric Cardiology, Department of Pediatrics, University of California, Los Angeles, School of Medicine, UCLA Center for the Health Sciences; and the Department of Medicine, University of California, Sun Diego, School of Medicine, La Jolla, California, USA Summary between these stimuli, other vasoactive agents, and the autonomic nervous system. The ductus arteriosus of the undisturbed fetal lamb was studied chronically by techniques that allowed direct serial measurements of the calibre of the fetal channel. When the direct actions were MATERIALS AND METHODS studied of vasoactive agents on the ductus arteriosus, prostaglan- Surgical and technical modifications of the sonocardiometry dins did not dilate the vessel beyond its resting dimensions. The methods previously reported from our laboratory (22, 24) were cyclooxygenase inhibitor, indomethacin, was a potent vasocon- utilized to study the intact fetal lamb ductus. One hundred and strictor with a plateau of the dose-effect relationship occurring at sixty-six experiments were performed on 42 time-dated pregnant 0.2 mg/kg. Fetuses of 95-98 days gestational age were equally ewes of mixed western breeds. The ewes were operated upon at sensitive to indomethacin when compared to animals near term. known gestational ages of 95-124 days (term = 148 days). Pre- Although the prostaglandins, PGEI, PGE2 PGFz., PGH2, PGI2 operative medication consisted of intramuscular meperidine (100 and PGGz, had no direct effect on the ductus arteriosus, PGE1, mg) and chlorpromazine (50 mg) for sedation and atropine (0.4 PGE2, PGH2 and PGIz reversed the vasoconstrictor action of mg) for minimizing secretions.
    [Show full text]