Hemodynamic Regulation of Arterial Endothelial Heterogeneity: Reductionist and Systems Approaches

Thursday, March 1, 2018 -
4:00pm to 5:00pm
The FUNG Auditorium
Peter F. Davies

Professor of Pathology & Laboratory Medicine and Bioengineering

Perelman School of Medicine

University of Pennsylvania


Richard Skalak Memorial Lecture

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-20th Century. Until the Renaissance, the prevalent theory of blood movement was that proposed by the 2nd Century Greek physician Galen as noncirculating ebb-and-flow systems associated with the primary organs. During the 15th and 16th 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 17th century, their dynamic regulatory involvement in homeostasis and pathology was delayed until the 19th 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.

Following training in Chemistry and Biochemistry, Dr. Davies received his Ph.D. in Experimental Pathology (Cardiovascular) in 1975 from Cambridge University (Darwin College). He received 2 years of postdoctoral training in cell pathology at the University of Washington, during which he was recruited to the Pathology faculty at Harvard Medical School 1978-88, with a concurrent Visiting Scientist appointment at MIT 1983-88. During the decade in Boston, he conducted pioneering flow experiments with Michael Gimbrone (HMS) and Forbes Dewey (MIT) that established the experimental basis of functional endothelial mechanotransduction. In 1988 he was recruited to the University of Chicago as full Professor where his innovative experimentation led to the decentralized model of endothelial mechanotransduction. At Chicago he was Director of the NIH SCOR in Atherosclerosis and actively interacted with the Argonne National Laboratory. In 1996, he was recruited to the University of Pennsylvania as founding Director of a new interdisciplinary Institute for Medicine & Engineering that he led for 16 years as Robinette Foundation Professor of Cardiovascular Medicine, Professor of Pathology, and Bioengineering. The Institute pioneered interdisciplinary research and educational initiatives between Medicine and Engineering Schools that have been widely adopted across campus and elsewhere. Since the Millenium, his research foci include transcription profiling of endothelial phenotypes as a function of hemodynamic environment in arteries and heart, and studies of cell-cell interactions in the artery wall, heart valve, and atherosclerotic lesions in relation to multiscale hemodynamics.

Dr. Davies' research has been continuously funded by the NIH since 1978 resulting in numerous publications in leading biomedical, biophysics and bioengineering journals. He also has over 20 years’ experience as Director of NIH Training Grants and successfully led a HHMI Interface Program. His strong interest in academic mentorship is reflected in over 60 graduate and postdoctoral trainees, the majority of whom remain in Academia. He was elected Chair of the AHA National Research Committee 1997-99. Throughout his career he has maintained extensive editorial board and NIH study section responsibilities and chaired numerous national and international Scientific Advisory Boards.

Among many honors received by Dr. Davies are a NIH MERIT Award, the CARIM Medal of the University of Maastrict, AHA Senior Research Scientist Award, the Sinclair Lectureship of the British Atherosclerosis Society, Invited Fellow at the Isaac Newton Institute for Mathematical Sciences at Cambridge University, and recently he received a rare ScD degree by Cambridge University for Research Distinction in Science, the highest earned degree (by examination) conferred by the university. From 2007-17 he was a member of the Board of Directors of the National Space Biomedical Research Institute of NASA (counter-measures for microgravity). Currently he is a Fellow of the AIMBE, Fellow of the AHA in 3 Councils, and was recently elected Fellow of the AAAS.