Regulation of Vascular Smooth Muscle Cell Function by Mechanical Strain by George Chen-Hsi Cheng

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Regulation of Vascular Smooth Muscle Cell Function by Mechanical Strain by George Chen-Hsi Cheng Regulation of Vascular Smooth Muscle Cell Function by Mechanical Strain by George Chen-hsi Cheng S.M., Massachusetts Institute of Technology, 1993 A.B., Harvard College, 1988 Submitted to the Harvard-MIT Division of Health Sciences and Technology in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Medical Engineering at the MIT LIBRARIES Massachusetts Institute of Technology , 96 June 1996 SCHERING C Massachusetts Institute of Technology, 1996 Signatureof Author Harvard-MITi'fsion of Healt Sciences and Technology May 1996 Certified by Richard T. Lee, Thesis Supervisor Assistant Professor of Medicine, Harvard Medical School Lecturer~Panrtmnt of Mechanical Engineering, MIT Accepted by _ ..................-- na u; .... ay, - ector Harvard-MIT Division of Health Sciences and Technology ;MASSACHUSETTS INSTI'UTEE OF TECHNOLOGY JUN 0 31996 LIBRARIES Regulation of Vascular Smooth Muscle Cell Function by Mechanical Strain by George Cheng Submitted to the Harvard-MIT Division of Health Sciences and Technology on May 24, 1996 in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy in Medical Engineering Abstract Although smooth muscle cells participate in the remodeling associated with atherosclerosis and other vascular diseases, the mechanisms by which these cells interact with their mechanical environment are incompletely characterized. This thesis serves to elucidate the capacity of smooth muscle cells to modulate their matrix and respond to mechanical loading. Because integrins mediate many cell-matrix interactions, the role of integrins in reorganization and mechanical contraction of collagen by smooth muscle cells was assessed in blocking antibody studies. Of the collagen-specific integrins (a(11, c2 p1, and CI31) found to be expressed by these cells, only the ct• and a2 integrins mediated smooth muscle cell adhesion to collagen. In addition collagen gel contraction was mediated by a 2, but not by ao or a3 integrins. Interestingly, gel contraction was inhibited by an anti-031 antibody known for its stimulatory effect on cell adhesion. To evaluate the mechanical regulation of smooth muscle cell function in a three- dimensional matrix, collagen gel cultures were subjected to uniaxial, unconfined compression. Sustained static compression led to a decrease in DNA and glycosaminoglycan synthesis, respectively, as measured by 3H-thymidine and 35S-sulfate incorporation. Decreased incorporation was not due to diffusive limitation of the radiolabel into the gel. A brief transient compression led to a delayed induction of DNA synthesis but a decrease in glycosaminoglycan synthesis. The induction of DNA synthesis increased with the compressive gel strain, and was mediated by autocrine release of FGF-2 as demonstrated by antibody-blocking studies and ELISA. Thus mechanical loading differentially regulates metabolic functions of smooth muscle cells in a three-dimensional culture. Cellular strain was hypothesized to control the release of FGF-2 from smooth muscle cells; however, these strains cannot be readily assessed theoretically or experimentally from the bulk gel strain. Thus, a second method which imposes homogeneous and biaxially uniform strains to monolayer cells was developed. Oscillatory strain induced FGF-2 release dependent on the amplitude (0-30%), frequency (0 - 1 Hz), and number of cycles of strain (0 - 10'). There was a strain amplitude-threshold (10%) below which FGF-2 was not released. Above this threshold, FGF-2 release increased with the frequency, amplitude, and cycle number, but was maximally released by only -102 cycles of strain. Thus cellular strain amplitude and/or strain rate tightly regulate the release of FGF-2 from vascular smooth muscle cells. In addition, heparin studies demonstrated that cellular strain causes a transfer of intracellular FGF-2 to the extracellular low-affinity receptors. Thesis Supervisor: Richard T. Lee, M.D. Assistant Professor of Medicine, Harvard Medical School Lecturer, Department of Mechanical Engineering, MIT Thesis Committee Chair: Alan J. Grodzinsky, Sc.D. Professor of Electrical, Mechanical, and Bioengineering MIT Thesis Reader: Peter Libby, M.D. Director of Vascular Medicine Brigham and Women's Hospital Thesis Reader: Roger D. Kamm, Ph.D. Professor of Mechanical Engineering MIT Acknowledgments I would first like to thank my thesis supervisor, Dr. Rich Lee. I first met Rich about five years ago while finishing the second year of med school and searching for a decent research project with which to kill the subsequent n years of my (then) young life. Although I must have met with at least a dozen investigators, it was through Rich's persistence that I joined his group and am here today writing about vascular smooth muscle cells. I am grateful for that persistence, because as it turns out all the other cardiologists with whom I met have since left Boston, and were it not for my decision I would probably be writing in Cleveland or not yet writing at all. Through the years I have learned a great deal and have received invaluable support from him in many capacities. His ability to exert a sublethal stress and respond appropriately to my oscillatory strain has played an essential role in the completion of this work. The lab meetings/free meals have also been critical. I thank the HST-MEMP program for financial support, Dr. Roger Mark for academic advice, and Keiko Oh for administering all the checks and for answering all my last minute questions. This work was also supported, in part, by the NIH MSTP program. My gratitude also goes to Dr. Elaine Lee, fellow grad student who tolerated my mess for three years before she (understandably) decided to graduate and leave. During the past year, I have missed the luxury of, without warning, turning my head to the left and griping to a receptive ear. Elaine was a constant source of personal and technical support, and her finishing the program with flying colors has been inspirational. In retrospect, Prof. Alan Grodzinsky must also be sorry that Elaine left, because the clutter on my desk has been mounting at an alarming rate ever since. I am fortunate to have worked in Al's lab. How I managed to get through without ever cutting a joint, I will never know. His expertise, guidance, and humor have contributed greatly to my work. I am especially thankful for his helping me get past "that same sentence" during the writing of this document. Dr. Peter Libby and members of his lab, including Marysia and Elyssa, have helped us on many aspects of the project. Without their assistance, we would still be growing our first batch of smooth muscle cells, not knowing, of course, that they are actually fibroblasts. Many of the turns taken in the research have been steered by Peter's helpful feedback. Prof. Roger Kamm has continued to support me through the years, as teacher, collaborator, and more recently thesis committee member. Prof. Martin Hemler and Dr. Feodor Berditchevski at the Dana-Farber Cancer Institute collaborated with us on the integrin study and have helped us with other technical issues along the way. I thank Prof. Martha Gray for introducing us to the biaxial strain device and for allowing us to collaborate on its further development. Matt Mikulics helped with many of the design modifications, and Dave Gerson was instrumental in producing multiple devices and performing the necessary strain validations. Special thanks go to Smruti Parikh and Bill Briggs for their technical assistance, maintenance of the lab, and ability to be in two places at the same time. Not only were they responsive to my occasional inordinate demands (i.e. I need a dozen flasks of cells tomorrow), but they assisted me in many experiments. This work would not have been possible without them. I also thank Grace Timlin and Lisa Cook for making my life easier. A number of people in the lab have made for an entertaining environment and/or have saved me from stumbling over the years -- Tom, Larry, Greg, Marc, Steve, Soph, Ann, Jen, Paula, Scott, Eliot, and many more. I have especially appreciated commiserating/strategizing with Minerva this past year. I also thank Linda for disrupting the daily humdrum and for basically running the entire show. I thank my parents for their endless love, support, and inspiration, and am grateful to my sister Deborah for sharing her infinite wisdom. Finally, much of this work is dedicated to Annie who probably knows it better than I do and has been by my side throughout. I assure her that I will not be reporting another experiment in excruciating detail any time soon. George C. Cheng May 1996 Table of Contents Abstract 3 Acknowledgments 5 List of Figures 10 List of Tables 18 Chapter 1. Introduction 19 1.1 Athero sclero sis .................................................................................................. 19 1.2 The Vascular Sm ooth M uscle Cell ...................................................................... 20 1.3 Mechanical Forces in Blood Vessels ................................................... 22 1.4 Evidence for Vascular Responses to Mechanical Loading ................................... 25 1.4 .1 In V ivo Studies ......................................................................................... 26 1.4.2 In Vitro Studies ...................................... 26 1.5 Limitations of Previous Studies ............................... 28 1.5.1 Response in a Three-dimensional Matrix......................... ................ 28 1.5.2 Relationship between Cellular
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