Microvascular Research: Biology and Pathology

David Shepro, PhD, ed
1732 pages. Burlington, Mass: Elsevier Academic Press; 2005. $299.00. ISBN 13:978–0–12–639510–5

Microvascular Research: Biology and Pathology is a 2-volume compendium comprising 5 parts, 167 chapters, and nearly 1200 pages devoted to a detailed understanding of the microcirculation. The book is edited by David Shepro, PhD, and an editorial board that reads like the “who’s who” in microvascular research. The textbook takes a modern day approach to gathering, organizing, and reporting information in an outline form, cognizant that new information is being generated and published at a rate that exceeds its ability to be truly up to date. Rather, the authors have taken the approach of focusing on key principals and their experimental basis as the foundation for each chapter. The editors promise to provide updates through Web offerings when salient and novel findings are published, remedying the issue of a textbook that is out of date before it is published.

In some cases, the respective chapters read as well-referenced outlines rather than comprehensive reviews. To the cognoscenti, such an approach may seem superficial, but to those whose scientific interests border on the field of microcirculation, the chapters are insightful and easily comprehensible, if not comprehensive.

The initial section is devoted to cell biology and defines the role of the endothelium, extracellular matrix, and autocrine and paracrine factors in the genesis of the microcirculation. The fundamental roles of endothlin-1 and vascular endothelial growth factor and their signaling in microvascular regulation are presented. New developments with respect to the role of interleukin-7, classically considered a growth and antiapoptotic factor in T- and B-cell maturation, are introduced as a critical link between hematopoietic and endothelial developmental lineages that governs the compartmentalization and homing of lymphocytes into lymphoid and nonlymphoid sites. Such integrative concepts are linked then to a discussion of the role of these factors in clinical disease states such as carcinogenesis. A similar important chapter on the structure and function of the capillary basement membrane provides an essential foundation for the understanding of the role of the extracellular matrix of the microvasculature in disease pathogenesis. The chapters on ephrins, neuropilins, and endothelial heterogeneity transition the discussion from microvasculature development to specialized differentiation. An important housekeeping detail is that not all of the most important illustrations are provided in color, and those that are must be accessed in an index at the end of each volume, which constitutes a minor inconvenience.

Section B on vasculogenesis and angiogenesis is a must-read for any interested but uninitiated scientists. In 7 nicely illustrated chapters, the authors provide a clear and referenced guide to aspects of these critical biological processes. The sections that discuss signaling mechanisms for vascular endothelial growth factor and platelet-derived growth factor are especially well done. Section C relates commonly utilized in vivo models used in the study of the microvasculature and is useful principally for scientists interested in developing these models in their laboratories. To me, its significance pales in comparison to the extensive offerings in the neighboring sections. Section D (on permeability, tone, and hemodynamics) is another must-read that is superb in relating the litany of factors, functions, and interactions of the microvasculature. Here, the fundamental roles of flow and shear stress and their transducers for signaling at a cellular and molecular level are discussed. Furthermore, the cellular mechanisms of vascular tone are related in detail in a series of nicely illustrated and well-referenced offerings. These chapters, rich in cellular-signaling mechanisms, are punctuated by several illustrations of organ-specific effects, including cytokine-induced pulmonary endothelial permeability (chapter 40) and vasomotor control in skeletal muscle (chapter 44), that presage the more detailed organ-specific conditions in part 3. Finally, section E discusses the role of the microvasculature in transport, adhesion, and inflammatory processes. Specifically, discussion of the role of selectins and their ligands, adhesion molecules, and integrins in mediating the respective processes of rolling, adhesion, and transmigration of leukocytes is particularly well done. In addition, there is ample attention paid to the functional significance of gap junctions and the dynamic actions of the connexin family of proteins (chapter 49).

I found the separation of “Organ Microvascular Adaptations” (part 2; 34 chapters) and “Organ Specific Pathologies” (part 3; 60 chapters) artificial and a bit distracting. For example, being a cardiologist with an investigative interest in coronary flow and vasodilator reserve, I read with great interest Dr Aird’s theoretical discussion (chapter 56) of the distinctions in endothelial function in the various components of the coronary microcirculation, but I needed to wait nearly 300 pages to find experimental illustrations of these principals. The subsequent discussion of “Coronary Slow Flow” (chapter 98) is a limited overview of microvascular angina, conspicuous for the absence of any mention of microvascular angina in hypertrophy, regional heterogeneity of microvascular flow and relationship to regional mechanical function, or the effects on functional flow reserve impairment attributable to extravascular compressive forces. Furthermore, there is no discussion of variant angina, the pathogenesis of which has evolved from myogenic and neurogenic dysfunction to a disease of the coronary endothelium in conduit vessels. Finally, it seems almost negligent to omit any discussion of coronary collateral formation or flow, particularly given the unique responses of coronary collateral vessels to physiological stimuli such as exercise and vasoconstrictive substances such as vasopressin.

The discussion of microvascular dysfunction in diabetes (chapter 99) similarly fails to consider the extraordinary work of Michael Brownlee’s laboratory that has provided a unifying mechanistic link between diverse metabolic effectors (advanced-glycation end products, polyol flux, hexosamine, and protein kinase C) and hyperglycemia as the common trigger. Moreover, the focus of the findings is exclusively on the role of endothelin. Although of laboratory interest, endothelin is a distant second as a pathological vasoconstrictor to the role of the angiotensin in mediating diabetic microvascular injury. Furthermore, diabetic microvascular injury in the kidney, manifest clinically as proteinuria, is preventable with either angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists. To date, despite the theoretical appeal, endothelin antagonists have not proved to be of clinical utility in other than idiopathic pulmonary hypertension. As such, the case for endothelin seems overstated in this context.

The chapter on “Ischemia Reperfusion Injury” (chapter 113) takes a similar and curious tangent, focusing on the role of natural antibodies and the complement cascade. Although these mechanisms may be relevant in ischemic bowel disease, there are few pathophysiological circumstances in which ischemia and reperfusion injury have been studied more extensively than the myocardium. Yet, there is no mention of the litany of mechanistic information on reperfusion injury and attempts at intervention in the postischemic myocardium. Moreover, at least a cursory discussion of flow-function match (myocardial hibernation) and mismatch (myocardial stunning) seems warranted, given the inextricable link between metabolic demands and microvascular function in the heart that is emphasized in chapter 56. At the same time, the somewhat limited discussion of microvascular dysfunction in cardiovascular disease states is surrounded by fascinating discussions of the role of the blood-brain barrier, renal medullary and cortical flow, and the relationship of angiogenesis to tumorogenesis among many others.

In the interest of full disclosure, I am a textbook “junkie” evolving in the world of information technology. As such, I found the nearly 1200 pages a very useful reference. The observation underscores the fact that the compendium is about fundamental principals of general interest to scientists in many disciplines. It is particularly suited for predoctoral students in the biomedical sciences given its breadth, if not its depth. As a senior investigator whose work spans a spectrum from myocardial metabolism, to simian immunodeficiency virus–induced myocardial inflammation, through to the effects of cocaine toxicity, the microvasculature is often “where it’s at.” Microvascular Research provides a useful compendium of microvascular models in a myriad of organ systems that is helpful in generating new hypotheses and approaches in any organ system of interest. Every integrative biology laboratory should own a copy.