Hemodynamic Regulation of Arterial Endothelial Heterogeneity: Reductionist and Systems Approaches

Considering the necessity of an efficient fluid transport system for evolution, it is astonishing that the fluid dynamics of mammalian blood flow and its associated biomechanical and biological consequences were largely ignored until the mid-20^th Century. Until the Renaissance, the prevalent theory of blood movement was that proposed by the 2^nd Century Greek physician Galen as noncirculating ebb-and-flow systems associated with the primary organs. During the 15^th and 16^th Centuries, Versalius and Da Vinci recognized inconsistencies of the Galen hypothesis (and Da Vinci extrapolated his interest in hydraulics to blood flow), but a complete circulation was only experimentally demonstrated a generation later by Harvey in 1628. Although microscopy revealed cellular structures in the 17^th century, their dynamic regulatory involvement in homeostasis and pathology was delayed until the 19^th century when cell biology was made more accessible by advances in dye chemistry and microscopy. Cellular pathology was accelerated by the German pathologist Virchow (d.1902) who introduced systematic autopsies and recognized that the cellular components of vascular tissue were prominent in mediating inflammation and coagulation, the latter exacerbated by sluggish flow (cf. Virchow’s Triad). Virchow also recognized the non-random distribution of atherosclerosis. In parallel, the mathematical basis of Newtonian fluid dynamics was firmly established in the physical sciences and a golden age of discoveries in biochemistry and physiology ushered in the development of modern hypothesis-driven experimental medical research.

The convergence of hemodynamics with cellular pathology accelerated in the 1960s largely through renewed interest in the endothelium by pathologists as an active - rather than passive – interface and by fluid dynamicists intrigued by the complexities of flow in blood vessels; this interest was catalyzed by the replacement of infection by cardiovascular disease as the leading cause of death in developed countries. While the endothelium was noted to be responsive to surgically-altered flow patterns in vivo, successful culture of endothelial cells in the 1970s was necessary to allow cause-effect mechanistic cell responses (reductionist) to be investigated by precise control of the local fluid dynamics with reference to in vivo flow; a large interdisciplinary sub-field of endothelial research has since fruitfully developed. During the past 2 decades the in vivo pathobiology of flow-related endothelial mechanisms have been enhanced by technical developments in genetics, molecular biology and svstems biology. Consequently the gap between reductionism and its integration into very complex cellular mechanisms operating in vivo has narrowed. I will describe some of my own experiences in addressing the interdisciplinary challenges of flow-mediated endothelial biology and its role in spatio-temporal endothelial heterogeneity in arteries with some emphasis on the valuable interplay of in vivo systems biology approaches and concomitant reductionist experiments at the bench. In doing so I recognize the contributions of mathematical analyses of model vessels and rheological systems with which Dick Skalak was a master.