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Hypoxic Pulmonary Vasoconstriction:
Cellular and Molecular Mechanisms
Jason X.J. Yuan MD, PhD (Editor), Boston, MA: Kluwer Academic Publishers, in 2004, 509 pp. $139 ISBN:1-4020-7857-9.
Hypoxic Pulmonary Vasoconstriction (HPV): Acute exposure to moderate alveolar hypoxia results in pulmonary vasoconstriction that onsets within seconds and is sustained for hours. HPV matches ventilation to perfusion and optimizes systemic oxygenation in the adult. In the fetus, HPV minimizes flow to the unexpanded lung whilst, in the newborn, reversal of HPV contributes to the fall in pulmonary vascular resistance that characterizes the transitional pulmonary circulation. HPV largely reflects the constriction of small, resistance pulmonary arteries. This homeostatic response is conserved and “HPV equivalents” are found in the gills of fish and the skin of amphibians. Chronic hypoxia, as occurs at altitude or with chronic lung disease, results in pulmonary hypertension.
In eight sections, 33 Chapters and 590 pages, Yuan’s multiauthored text provides a well-referenced account of virtually every aspect of HPV. The book introduces the reader to the study of the effects of acute and sustained hypoxia on the pulmonary circulation and the information is relevant to medicine, physiology and cell biology. The chapters deal with pulmonary vascular physiology and the many hypoxic responses, both acute (altered production of reactive O2 species, ion channel modulation, elevation of cytosolic calcium, activation of the contractile apparatus) and chronic (activation of hypoxia inducible factor, altered gene transcription, enhanced cell proliferation and impaired apoptosis). The text includes discussion of both HPV and certain forms of pulmonary hypertension, reflecting the intersection of these phenomena. The book is aimed at physiologists and basic scientists, rather than physicians. It is an ideal reference text for trainees or faculty interested in oxygen sensing, high altitude physiology or pulmonary hypertension.
The contributing authors are acknowledged leaders in the field and, in an ecumenical gesture, labs with diametrically opposing views have chapters in the text. This is a strength of the book, ensuring the details of a particular theory are fully aired; however, it does require the reader to be discerning and to use information from multiple chapters to weigh opposing theories and define probable truths. Being a multi-authored text it reflects the many differences of opinion regarding the mechanism of HPV and chronic hypoxic pulmonary hypertension extant today.
The reader will encounter diametrically opposed views on the mechanism of HPV. A compilation of opposing chapters might read as follows: The pulmonary vascular O2 sensor is in the smooth muscle (versus the endothelium), and is based on the production of reactive O2 species in the mitochondria (versus NADPH oxidase). Hypoxia signals HPV by creating fewer reactive O2 species during hypoxia (versus more) thereby inhibiting voltage gated potassium channels (versus TASK channels) and causing membrane depolarization. Cytosolic calcium is ultimately increased by activating the L-type calcium channel (versus enhancing release of calcium release from the sarcoplasmic reticulum) and this results in activation of the contractile apparatus (versus minimal changes in cytosolic calcium but enhanced calcium sensitization resulting in HPV). This conveys the Tower of Babel that is HPV research in 2005. Thus, the onus is on the reader to carefully weigh the evidence. In many cases the chapters tend to pursue a single point of view rather than acting as a weighted review. Still, the chapters, with few exceptions, are well-written and present their case clearly. Consensus gradually emerges when the reader compares facts between chapters and sections. For example there is good agreement on the role of O2 sensitive K+ channels and HPV in most chapters and this mechanism is supported by the chapters dealing with O2 sensing in other specialized tissues, such as the carotid body.
The book is organized into eight sections. It begins with chapters on the Physiology and Pathophysiology and features an elegant review of fundamental work on the basic properties of HPV by Charles Hales, who is well positioned as an author, having made major contributions to the field. The chapter on heterogeneity of HPV, written by the late Chris Dawson, is a pleasure to read and reminds the reader that HPV is not only unique to the pulmonary circulation but is preferentially manifest in specific zones of the vasculature. One is also reminded that the Pulmonary Circulation community is poorer for the untimely loss of this quiet but insightful scientist.
Section 2, “The Role of Intracellular Calcium and Calcium Sensitization,” deals with the sources of calcium that elicit HPV, covering the contributions of calcium sparks, intracellular stores and calcium entry via the L-type channels. A highlight is a nice chapter by Robertson and McMurtry on the subject of calcium sensitization, a hot area in HPV research and one with therapeutic potential in chronic hypoxic pulmonary hypertension, e.g. rho kinase inhibitors.
In section 3, “The Role of Ion Channels,” there is substantial concordance, although not unanimity, regarding the important role of O2-sensitive K+ channels in the pulmonary artery smooth muscle cell in initiating HPV. Chapters by Smirnov, Archer and Yuan would all suggest that one or more voltage gated K+ channel plays a pivotal role in initiating HPV. A potential role for Trp channels, involved in capacitative calcium entry, is nicely summarized by Gurney.
Section 4 deals with “Endothelium-Dependent HPV.” This single chapter describes endothelium dependent and independent phases of the hypoxic constriction observed in isolated PA rings.
Section 5, “Oxygen Sensing in the Pulmonary Vasculature,” begins with a nice review of the role of reduction/oxidation chemistry (Lisa Palmer) and oxidant signaling (Mike Wolin) in the pulmonary circulation, reflecting a growing feeling the reactive O2 species may serve as vasoactive messengers in the pulmonary circulations. Sub-sequent chapters deal with putative O2 sensors, including redox state (Ken Weir), mitochondria (Navdeep Chandel, Evangelos Michelakis) and cADP ribose (Mark Evans).
Section 6 discusses “Oxygen Sensing in Other Tissues.” This section is helpful in weighing the sometimes-confusing information about the mechanism of HPV. These well-written chapters indicate a conserved role for O2 sensitive K+ channels in these nonvascular components of the body’s specialized O2 sensing system, including the carotid body, adrenomedullary cells and PC-12 cells. They put section 5 into perspective, acting as an “independent vote” for a conserved mechanisms of O2 sensing.
Section 7 deals with the “Pathophysiology of Chronic Hypoxic Pulmonary Hypertension.” This section is less thematically consistent than others and covers an eclectic mix of vascular remodeling in response to
chronic hypoxia, hypoxic modulation of transcription factors and gene expression, diversity in the propensity of smooth muscle cell types to hypoxic proliferatation, polyamine biosynthesis and remodeling, and strain differences in hypoxia sensitivity amongst rats. Section 7 contains an excellent “Bench to Bedside” overview of Primary Pulmonary Hypertension of the Newborn by Abman and Steinhorn. The practical mix of clinical information, physiology and basic science makes for an informative and easy read.
The final section reviews “Experimental Models of HPV” summarizes the models and techniques used to study HPV, laying out pros and cons. Madden and Gordon do a nice job of highlighting the double edged sword of “reductionist science” as pertains to the use of isolated arteries and cells in characterizing the mechanism of HPV. There is also a section on the patch clamp technique and the making of knockout mice, although these could be better integrated into the book. A suggestion for the second edition would be to include a summary at the end of each section where areas of agreement amongst authors and controversies could be explicitly listed.
Yuan, by allowing free voice to the research community, has provided us with a worthwhile, dynamic snapshot of the “State of the Art” in understanding acute and chronic pulmonary vascular O2 response, almost 60 years after the first modern description of HPV (1).
Stephen L. Archer
University of Alberta, Alberta, Canada
Reference
1. von Euler, U. & Liljestrand, G. Observations on the pulmonary arterial blood pressure in the cat.
Acta Physiol Scand 12, 301-320 (1946).
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