Eur Respir J 2008; 32: 1639–1651 DOI: 10.1183/09031936.00013908 CopyrightßERS Journals Ltd 2008 SERIES ‘‘HYPOXIA: ERS LUNG SCIENCE CONFERENCE’’ Edited by N. Weissmann Number 6 in this Series Regulation of hypoxic pulmonary vasoconstriction: basic mechanisms N. Sommer*, A. Dietrich#, R.T. Schermuly*, H.A. Ghofrani*, T. Gudermann#, R. Schulz*, W. Seeger*, F. Grimminger* and N. Weissmann* ABSTRACT: Hypoxic pulmonary vasoconstriction (HPV), also known as the von Euler–Liljestrand AFFILIATIONS mechanism, is a physiological response to alveolar hypoxia which distributes pulmonary capillary *University of Giessen Lung Center, Medical Clinic II/V, Justus-Liebig- blood flow to alveolar areas of high oxygen partial pressure. University Giessen, Giessen, and Impairment of this mechanism may result in hypoxaemia. Under conditions of chronic hypoxia #Philipps-University Marburg, generalised vasoconstriction of the pulmonary vasculature in concert with hypoxia-induced Institute of Pharmacology and vascular remodelling leads to pulmonary hypertension. Although the principle of HPV was Toxicology, Marburg, Germany. recognised decades ago, its exact pathway still remains elusive. Neither the oxygen sensing CORRESPONDENCE process nor the exact pathway underlying HPV is fully deciphered yet. The effector pathway is N. Weissmann suggested to include L-type calcium channels, nonspecific cation channels and voltage- University of Giessen Lung Center dependent potassium channels, whereas mitochondria and nicotinamide adenine dinucleotide Medical Clinic II/V Justus-Liebig-University Giessen phosphate oxidases are discussed as oxygen sensors. Reactive oxygen species, redox couples 35392 Giessen and adenosine monophosphate-activated kinases are under investigation as mediators of hypoxic Germany pulmonary vasoconstriction. Moreover, the role of calcium sensitisation, intracellular calcium Fax: 49 6419942419 stores and direction of change of reactive oxygen species is still under debate. E-mail: [email protected] In this context the present article focuses on the basic mechanisms of hypoxic pulmonary Received: vasoconstriction and also outlines differences in current concepts that have been suggested for January 29 2008 the regulation of hypoxic pulmonary vasoconstriction. Accepted after revision: May 02 2008 KEYWORDS: Hypoxia, hypoxic pulmonary vasoconstriction, lung, oxygen, oxygen sensing ypoxic pulmonary vasoconstriction altitude or during respiratory diseases (including STATEMENT OF INTEREST None declared. (HPV) is a physiological self-regulatory chronic obstructive pulmonary disease, sleep H response to alveolar hypoxia that distri- apnoea, fibrosis, failure of ventilation due to butes pulmonary capillary blood flow to areas of neurological diseases), may lead to general high oxygen availability. This principle, also vasoconstriction of the pulmonary vasculature known as the von Euler–Liljestrand mechanism, inducing vascular remodelling processes with thereby optimises gas exchange at the blood–air subsequent right heart hypertrophy and cor interface [1, 2]. pulmonale. Impairment of this mechanism during patho- Due to the opposite functions of lung vessels and logical situations in lung or systemic disease (for systemic vessels, collecting and distributing oxy- example, adult respiratory distress syndrome [3] gen, respectively, different reactions to hypoxia or hepatopulmonary syndrome [4]) or during have developed. Whereas most systemic vessels anaesthesia [5], may result in insufficient oxygen- of adult organisms dilate during hypoxia, pul- ation of arterial blood and poor oxygen supply to monary vessels constrict. During embryonic the body. Chronic hypoxia, as it occurs at high development lung vessels exhibit pronounced Previous articles in this series: No. 1: Wagner PD. The biology of oxygen. Eur Respir J 2008; 31: 887–890. No. 2: Zhou G, Dada LA, Sznajder JI. Regulation of alveolar epithelial function by hypoxia. Eur Respir J 2008; 31: 1107–1113. No. 3: Berchner-Pfannschmidt U, Frede S, Wotzlaw C, Fandrey J. Imaging of the hypoxia-inducible pathway: insights into oxygen sensing. Eur Respir J 2008; 32: 210–217. No. 4: Le´vy P, Pe´pin J-L, Arnaud C, et al. Intermittent hypoxia and sleep-disordered breathing: curent concepts and perspectives. Eur Respir J 2008; 32: 1082–1095. No. 5: Lo´pez-Barneo J, Ortega-Sa´enz P, Pardal R, Pascual A, Piruat JI. Carotid body oxygen sensing. Eur Respir J 2008; 32: 1386–1398. European Respiratory Journal Earn CME accreditation by answering questions about the article. You will find these at the back of the printed copy of this Print ISSN 0903-1936 c issue or online at www.erj.ersjournals.com/current.shtml Online ISSN 1399-3003 EUROPEAN RESPIRATORY JOURNAL VOLUME 32 NUMBER 6 1639 REGULATION OF HPV N. SOMMER ET AL. vasoconstriction, in order to minimise blood flow through the SIGNAL TRANSDUCTION AND EFFECTOR MECHANISM: noninflated lungs, and to preserve the foetal circulation. After ABOUT CONTRACTION AND CALCIUM birth, pulmonary oxygenation, in concert with lung inflation, The pathways leading to contraction of the PASMCs converge leads to vasodilation and perfusion of the lung. From the in an intracellular calcium increase and include the influx of ontogenic point of view, therefore, HPV also can be seen as extracellular calcium and release of intracellularly stored ‘‘normoxic pulmonary vasodilation’’ [6]. calcium [30]. The present article focuses on the basic mechanisms and For calcium influx from the extracellular space there is features of HPV, and also outlines differences in current evidence that both, L-type calcium channels [31, 32] and concepts that have been suggested for the regulation of HPV. nonspecific cation channels (NSCC) are involved. In line with Further research will be necessary to completely elucidate the this suggestion, inhibition of L-type calcium channels only molecular pathways underlying HPV, which may serve as a partially abolished HPV [33, 34], whereas inhibition of NSCC basis for the development of new therapeutic strategies to treat completely inhibited HPV [35–37]. Hypoxic regulation of the disturbances in gas exchange caused by impaired HPV and L-type calcium channels may be achieved by direct modula- pulmonary hypertension caused by exacerbated HPV. tion via reactive oxygen species (ROS) or membrane depolar- isation via potassium channels [38–40] and NSCCs. CHARACTERISTICS AND KINETICS OF HPV Different types of potassium channels have been demonstrated HPV is a highly conserved mechanism, present in most to be involved in hypoxia-associated membrane depolarisa- mammals [7–10], partially in reptiles [11] and probably even tion, particularly the voltage-gated potassium (Kv) channels, in fish [12]. Although an increase in pulmonary arterial Kv2.1, Kv1.5, Kv9.3 [41–43], which have been suggested to be pressure in response to alveolar hypoxia was recognised early the ‘‘first step’’ in HPV. However, only partial inhibition of [13, 14], it was in 1946 that von EULER and LILJESTRAND [15] HPV in knockout animals suggests this may not be the sole suggested that ventilation-perfusion matching was the pur- mechanism of HPV [44]. The concept of Kv channels being pose of this response. Subsequently HPV was demonstrated to directly regulated by redox-changes has been proposed by be present in humans, determined by a 50% increase in POST et al. [39]. The Kv channels may be regulated by: 1) pulmonary arterial resistance to an alveolar oxygen partial reducing agents [45–48], such as glutathione (GSH) [49]; 2) an pressure (PA,O2) ,50 mmHg (,6.66 kPa) [16]. Since then, associated haemoprotein; 3) membrane depolarisation; or 4) a factors modulating HPV have been identified by dissecting calcium increase triggered by intracellular calcium release the mechanism of HPV using a variety of approaches including from intracellular stores or via NSCCs. Thus NSCCs may be isolated organs, tissues and single cells. Modulating factors key channels for hypoxic signalling, for example, in the include sex, local and circulating vasoactive substances, pH, regulation of potassium channels, of L-type calcium channels partial pressure of carbon dioxide [17, 18] and red blood cells, or the calcium level. The NSCCs have recently been empha- although there was an early consensus that the mechanism sised as potential key regulators in HPV [37]. They consist of a itself was independent from neural [19] or humoral [20, 21] group of store-operated and receptor-operated calcium chan- triggers. nels (SOCs and ROCs, respectively), and their molecular identity has been revealed as transient receptor potential In the isolated, buffer-perfused lung, HPV is activated at a (TRP) channels. Certain subtypes of the TRP channels have partial pressure of oxygen (PO2) ,100 mmHg (,13.3 kPa) [8, been demonstrated to be increased in rat pulmonary arteries 10]. The precapillary smooth muscle layer of the resistance (PAs) after exposure to chronic hypoxia and human PASMCs vessels, located at the entrance of the acinus has been in idiopathic pulmonary hypertension, suggesting a patho- identified as the effector cell-type for HPV [22–25]. genetic importance of TRP canonical (TRPC)1 and TRPC6 [50, Pulmonary arterial smooth muscle cells (PASMC) contract in 51]. The SOCs play a role in capacitative calcium entry (CCE), a response to hypoxia at a PO2 of 25–50 mmHg (3.33–6.66 kPa), calcium influx from extracellular space that can be induced by particularly in resistance arteries, whereas smooth muscle cells emptying intracellular stores,