Introduction

Rationale and Reader's Guide

I can safely state that no one truly comprehends the physiology and pathophysiology of the microvasculature. In a large measure, this less than desirable state is the result of an explosion of new scientific data that creates paradoxically [or maybe poetically] a concomitant explosion of ignorance. But challenges enhance curiosity. Regardless how far scientists' understanding may be from the natural laws that regulate microvessel functions, we share an incumbency to accumulate and disseminate, by whatever means, current new concepts based upon the latest tested investigations. Hence, the Biology and Pathology Microvasculature Research in printed and electronic formats. As Lord Florey once stated: "I do not think there is any sharp line between physiology and experimental pathology," hence the subtitle.

In 1967, at a Boston conference the Microcirculation as Related to Shock, (D. Shepro and G.P. Fulton, Eds. Acad. Press, 1968) Robert Ebert, then dean of Harvard Medical School, summarized the proceedings in his keynote address that: "in shock all physiological parameters are disturbed but if there is a common denominator it would be the microcirculation."

Endothelium is metabolically one of the most active tissues in the body . . . probably second only to nervous tissue. Microvessels bridge the subcellular to the cellular to the organ to the system. The breaching of the microvascular barrier is part and parcel of every disease. An inflammatory response, initially localized by microves-sels, is frequently a persistent parameter of every disease. Hence, whatever the therapeutic intervention, continuous attenuation of this defense mechanism, when awry, is required. As a closing but not a final argument, one important current concept is that there are specific microvas-cular diseases that to a large extent are independent of events in other parts of the cardiovascular system; e.g. angina with patent coronary arteries, cardiac slow flow states, long flight induced edema. Some scientists have speculated that the first stage of all forms of dementia is a breakdown of the blood brain barrier.

In the past, writers and publishers at some point had to agree on an endpoint, regardless of the manuscript's blemishes, and submit what was on hand for publication. As the "ink dried," the accumulated responses from critics and readers and new information would form the basis to kickoff a new edition, more frequently than not, years after the initial publication. Informatics technology, in all research endeavors, adds a new dimension to publishing, namely instant editing when the need arises, whether it be daily, weekly, quarterly, biannually. Because the editors and publishers are mindful of the fact that the currency of each scientific publication devaluates rapidly, the electronic version of Microvascular Research will be updated frequently. If "break throughs" should occur, an epilogue can be added immediately or reverse, obsolete "facts" and speculations that do not dovetail with new documented data can be immediately deleted.

The readers will quickly note that each presentation is limited to about 10-15 printed pages, unusual especially for review articles, and with a limited annotated (author's) bibliography. This editorial decision is based upon the realization that investigators are swamped with data and with the new tools to share information, speed has become an essential parameter. Global updating is so easily and readily available that, less can be an advantage. Given the space constraints, our contributors are challenged to provide the readers with their best objective and subjective take on the state of their sub-discipline. The redeeming fall-out of condensation is that lengthy introductions, redundant citations, speculations beyond the call, are eliminated. The creative sifting and contracting prior to submitting an article serves as a needle's eye.

A Perspective on Historical Recordings

In keeping with the editorial consensus that brevity can be a virtue and in light of the speed of scientific discoveries [see Rationale], a classical account that chronologically recapitulates microcirculatory milestones is not included in the volume. Some readers will regard this decision as an intellectual miscalculation; that without a record of discoveries there is blinding ignorance. Yet, it is an accepted fact of academia that recorders of events cannot prevent their imaginations from slipping into their "factual accounts." The noted historian Pieter Geyl states "history is an argument without end". For example: Who was the first to posit the existence of capillaries and their connecting role : Erisistratus? Galen? Malpighi? Harvey? Leeuwenhoek? Boerhaave? Henle? The winner of the paternity title will go to the histiographer of your choice. Fortunately, a wealth of microcirculatory data are readily available in paper and electronic format, which lessens the need for such a chapter in the Encyclopedia. However, to accent the editors' recognition and appreciation of history, an illustration may provide the wherewithal to unravel one scientific puzzle in the history of microvascular research.

Why did it take over a century for scientists to appreciate the heterogeneity and high metabolic activity of the ubiquitous endothelial cell [not to mention the pericyte]? Elie Metchnikoff (1883), at the Pasteur Institute, in describing his new theory on inflammation that laid the foundation for the modern concept of this defense mechanism, stated:

"Movement [contractility] of endothelial cells plays an important role in the formation of stomata during inflammation as Klebs thought and as I imagined and stated in my first paper on inflammation."

Another Nobel laureate, August Krogh, described and illustrated endothelial cell motility in "The Anatomy and Physiology of Capillaries" [1922], the publication of his Sterling Lectures given at Yale University. Although both works are highly quoted, the scientific concepts that they embrace were virtually ignored in endothelial research until a scant 30 years ago. In 1966, the laureate Lord Florey, in his address entitled, "The Endothelial Cell", honoring the noted pathologist Sir Roy Cameron, spoke exclusively on the morphology of these cells. Presciently, he concluded that his was an interim report and "I should expect to see in the next ten years a rich harvest of new [functional] knowledge. ..."

Again the question—why the achievements of three laureates, whose collective contributions significantly codified microvascular biology, were largely ignored? One explanation certainly can be argued on the importance of technology over imagination; that in the life sciences technology has always played a dominant role (review the history of the microscope) in contrast to Newton's and Einstein's science, where imagination was dominant. In other words, the technology for accurately profiling mural cells was unavailable. But in this scientific teaser I believe the answer lies in the incandescence of another stellar scientist, Earnest H. Starling, whose hypothesis on fluid transport still remains a major physiological principal. But for years this monumental work may have put blinders on investigators regarding the true nature of the microvascular wall. The Starling quotation in part supports this opinion:

"We have no sufficient evidence to conclude that endothelial cells of capillary walls take any part in the formation of lymph " [1896]

The elegance of Starling's hypothesis and research on filtration was so convincing that for decades microvascular physiologists devoted their efforts, for the most part, to fine tuning his formula. I hasten to add that this opinion does not diminish Starling's achievements and legacy an iota. Newton's unique contributions were eventually and correctly challenged and even the theories of Einstein, the genius of the 20th century, are now under scrutiny.

I would add one very personal speculation (a chronicler's prerogative) that might explain why Starling ignored other scientific data that could have affected his unilateral view of the microvessel wall as a passive barrier. Notwithstanding their correspondence on science and other matters, Starling did not appear to appreciate Krogh's experimental data. My perception is that he viewed Krogh as a junior level scientist and I "imagine" he was a tad jealous of his Danish colleague's talents.

In summary, I respectfully suggest to those who are interested in the historical analysis of microcirculation to select the format that best matches their interest. The chronological approach is the most common and of course should include examples from ancient oriental cultures as well as those from western civilization. Another choice would be to select the superstars of different eras. For example, Andreas Vesalius's "De Humani Corporis Fabrica" could be the starting point of modern science since this publication marked the deathknell for skewing scientific data to comply with authority (Aristotle; Galen). Vesalius's work was based on careful observations. Would there have been a Harvey [17 century] without a Versalius [16 century]? Advances in technology, such as the history of the microscope, can also be an artful approach to chronicle advances in microcircula-tory knowledge. Whatever your choice, the endpoint will be similar.

References

Florey, H.W. 1966. The endothelial cell. Brit. Med. J. 27: 487-490 Krogh, A. Anatomy and Physiology of Capillaries. New Haven: Yale University Press. 1922. pp. 47-69 Metchnikoff, E. Lectures on the Comparative Pathology of Inflammation.

New York: Diver Publications, Inc., 1968. pp. 137-156. Starling. E.H. 1896. On the absorption of fluids from connective tissue spaces. J. Physiol. Lond. 19: 312-326

Acknowledgements

I thank all of the contributors, the editors who developed and shaped the contents of these volumes, our Elsevier Editor, Noelle Gracy, who inaugurated the project, and provided often needed encouragement, notwithstanding a transfer to Holland and a maternity leave. And to Karen Dempsey, at Elsevier, San Diego, who managed to organize our input, in bits and pieces, into a professional, valuable publication—always positive in her responses and never displays an "ounce of static." To my assistant, Christina Pitcher-Cozzone, for her "can do" handling of correspondence and almost daily revisions of contributors, titles and contents. Lastly, my gratitude to my wife, Marilyn, for her encouragement whenever I whined about the problems of a head editor and who did not complain about lengthy disappearances to my computer during the final stages of production.

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