Stephen M. Schwartz

Dr. Schwartz's career has covered many areas of vascular biology. He has also trained several investigators who have gone on to become major figures in vascular biology research in their own right.
The major effort of Dr. Schwartz's laboratory is on growth control of vessel wall cells and smooth muscle lineages. The work is largely based on concepts of cell cycle regulation derived from research in developmental biology and tumor biology applied here to therosclerosis and hypertension. The laboratoryhas shown that smooth muscle cells belong to distinct lineages or subsets. Unique properties of these subsets may account for monoclonality of atherosclerotic lesions and for the special properties of the arterial intima that contribute to progression of atherosclerosis. Most of the lab's effort is directed at specific functions of subsets as dictated by their characteristic patterns of gene expression. These functions include subset-specific promoter function, contraction of gels by adhesive proteins, and control of programmed cell death.

Current projects include: 1) Clonal variation in lineage-specific genes by smooth muscle cells from blood vessels; 2) Role of cell adhesion molecules in plaque contraction; 3) Identification of lineage-specific genes by rapid sequencing; 4) Role of apoptosis in vascular remodeling. Current cloning efforts in the lab are directed at identifying new genes that are specific for human smooth muscle subsets.
Endothelin Structure Function: Ph.D. Thesis under Dr. Earl Benditt.

Dr. Schwartz's interest in blood vessels began at Harvard College, where he studied electron microscopy with Dr. Keith Porter, and in Medical School under Dr. Guido Majno. After Medical School, Dr.stinct functions in vivo. Genes cloned on the basis of belonging to the * phenotype in vitro also appear to mark the intimal phenotype seen in atherosclerosis and in the neointima that appears after injury. Continuing in this line, Dr. Giachelli has cloned other pup-intimal genes and hasshown that these may play a critical role in the vascular response to injury. One of these genes, osteopontin, plays intriguing roles in migration and proliferation of smooth muscle cells and is a major focus of this lab. As already noted, we now havean extensive effort focused on the biology of osteopontin including embryology and function. As part of this effort we identified the receptors for osteopontin. One of these, integrin *v*3, may play a key role in smooth muscle and endothelial migrationafter injury. We now have evidence that *v*3 may mark subsets of smooth muscle in humans. The integrin *3 has also been shown to identify a subset of smooth muscle cells in humans. A graduate student, Ms. Laura Smith, is working on the mechanisms controllingexpression. Ms. Karen Yee, also a graduate student, is studying mechanisms controlling gel extraction.

Studies in Humans: Dr. Schwartz's interests have gradually moved into human studies. Fellows and colleagues critical to this effort have includedDrs. Giachelli, David Gordon, Edward O'Brien, and Charles Murry. Dr. Gordon was the first person to validate a cell kinetic method in the human vessel wall and to show, with Dr. Schwartz, that replication at best is a small part of the advancedatherosclerotic lesion. Dr. O'Brien extended the application of these methods to show that restenosis in humans is probably not due to smooth muscle replication. This has led to new studies of mechanisms of remodeling and the role of intimal cells in this process. Recently Dr. Schwartz's group has revisited an old issue in an effort to look at the atherosclerotic lesion from a different point of view. Dr. Murry, working with other fellows in the group, has developed a set of methods that allow the application of several molecular biologic methods to tissues on slides. One of these methods has allowed Dr. Murry to microdissect slides, demonstrate that plaques are indeed monoclonal, and identify the monoclonal cell -- the smooth muscle cell of the plaque cap.

Dr. Murry's demonstration of monoclonality confirms earlier work by Dr. Schwartz's mentor, Dr. Benditt, and opens up a new area of research -- the attempt to identify the genetic basis for monoclonality. Efforts in the latter direction are beginning to bear fruit. Another fellow, Dr. Bennett, has shown an apoptotic mechanism that is unique to the plaque-derived smooth muscle cell. Current cloning efforts in the lab are directed at identifying new genes that are specific for human smooth musclesubsets. Ongoing efforts in collaboration with Drs. Joseph Miano and Eric Olson have identified homeobox genes, Hox B7 and C9, as distinctive to certain smooth muscle subsets.